WO2013046029A1 - Inhibiteurs macrocycliques de la kinase lrrk2 - Google Patents

Inhibiteurs macrocycliques de la kinase lrrk2 Download PDF

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Publication number
WO2013046029A1
WO2013046029A1 PCT/IB2012/002318 IB2012002318W WO2013046029A1 WO 2013046029 A1 WO2013046029 A1 WO 2013046029A1 IB 2012002318 W IB2012002318 W IB 2012002318W WO 2013046029 A1 WO2013046029 A1 WO 2013046029A1
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Prior art keywords
alkyl
het
halo
optionally
mmol
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PCT/IB2012/002318
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English (en)
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Jan Hoflack
Petra Blom
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Ipsen Pharma S.A.S.
Oncodesign S.A.
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Priority to RU2014117515A priority Critical patent/RU2622104C2/ru
Priority to UAA201404562A priority patent/UA113186C2/uk
Application filed by Ipsen Pharma S.A.S., Oncodesign S.A. filed Critical Ipsen Pharma S.A.S.
Priority to CA2850350A priority patent/CA2850350A1/fr
Priority to KR1020147011284A priority patent/KR20140095477A/ko
Priority to BR112014007654A priority patent/BR112014007654A8/pt
Priority to MX2014003557A priority patent/MX342177B/es
Priority to JP2014532498A priority patent/JP6082397B2/ja
Priority to AU2012314035A priority patent/AU2012314035B2/en
Priority to EP12798824.4A priority patent/EP2760453B1/fr
Priority to CN201280058430.8A priority patent/CN104023728B/zh
Priority to US14/348,138 priority patent/US9096609B2/en
Priority to DK12798824.4T priority patent/DK2760453T3/en
Priority to ES12798824.4T priority patent/ES2583477T3/es
Publication of WO2013046029A1 publication Critical patent/WO2013046029A1/fr
Priority to HK15100389.2A priority patent/HK1199838A1/xx
Priority to US14/747,882 priority patent/US9370520B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/18—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/504—Pyridazines; Hydrogenated pyridazines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/529—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/16—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/16—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D515/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D515/16—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D515/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D515/18—Bridged systems

Definitions

  • the present invention relates to novel macrocylic compounds and compositions containing said compounds acting as kinase inhibitors, in particular as inhibitors of LRRK2 (Leucine-Rich Repeat Kinase 2). Moreover, the present invention provides processes for the preparation of the disclosed compounds, as well as methods of using them, for instance as a medicine or diagnostic agent, in particular for the treatment and/or diagnosis of diseases characterized by LRRK2 kinase activity such as neurological disorders including Parkinson's disease and Alzheimer's disease.
  • LRRK2 Leucine-Rich Repeat Kinase 2
  • Parkinson's disease is a degenerative disorder of the central nervous system. It results from the death of dopaminergic neurones in the midbrain. In the early stages of the disease the most obvious symptoms are movement-related such as shaking, slowness of movement and difficulty with walking. Later on also cognitive and behavioural problems arise, with dementia commonly occurring in the advanced stages of the disease. Although Parkinson's disease is generally considered to be sporadic, within the last decade, a few mutations in the LRRK2 (leucine rich repeat kinase 2) gene have been linked to Parkinson's disease (WO2006068492 and WO2006045392).
  • LRRK2 leucine rich repeat kinase 2
  • LRRK2 also known as dardarin
  • LRRK2 is a member of the leucine-rich repeat kinase family having mixed-lineage kinase activity, in particular in the brain, but also in other tissues throughout the body.
  • researchers have identified over 20 LRRK2 mutations in families with late-onset Parkinson Disease.
  • the G2019S mutation co-segregates with autosomal dominant Parkinsonism and accounts for about 6% of familial Parkinson's disease cases and 3% sporadic Parkinson's disease cases in Europe.
  • the G2019S mutation occurs in the highly conserved kinase domain and it has therefore been postulated that the G2019S mutation may have an effect on kinase activity (WO2006068492).
  • amino acid substitutions at a second residue R1441 are also associated with Parkinson's disease and have also been shown to elevate LRRK2 kinase activity.
  • Over-expression of the mutant LRRK2 protein R1441 G in transgenic mouse models Li, Y et al.
  • LRRK2 Alzheimer's disease
  • argyrophilic grain disease Pick's disease
  • corticobasal degeneration inherited frontotemporal dementia
  • Parkinson's disease Two further mutations in LRRK2 have been clinically associated with the transition from mild cognitive impairment to Alzheimer's disease (WO200714979).
  • LRRK2 kinase inhibitors in particular those for the treatment of neuronal disorders, do not comprise macrocyclic pyrazolopyrimidine moieties (see for example WO2009127652, WO201 1038572).
  • macrocyclic compounds described herein act as kinase inhibitors, in particular LRRK2 kinase inhibitors.
  • the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof,
  • 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -O-d-ealkyl, -S-d -6 alkyl, -Het 3 , -Ar 2 , -NR 13 R-
  • R 4 is selected from -halo, -OH, -d-ealkyl, -0-C 1-6 alkyl, -S-C 1-6 alkyl, -NR 17 R 18 , -Het 4 ;
  • each of said C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Od- ealkyl, -Sd. 6 alkyl, -Het 5 , -N R 23 R 24 ;
  • R9i Rl0> Rl 1 i l2i Rl3i l4i Rl5i Rl6> Rl7> Rl8i Rl9> R2C Rzi > R ⁇ 2> R23> R24> R ⁇ 5> R26> R ⁇ 7> R281 R29.
  • R30, R31 , R32, R33, R34, R351 Rse, R37, 38, R39 and R 40 are each independently selected from -H, -halo, -O, -OH, -0-C 1-6 alkyl, -C -6 alkyl, -G 3 . 6 cycloalkyl or -Het- ⁇ ; wherein each of said
  • 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from
  • C ⁇ alkyl, -(C 0)-NR 3 -d-ealkyl-, -NR 3 -d. 6 alkyl-, -d-ealkyl-NRg-d-ealkyl-, -S0 2 -NR 3 -; wherein each of said C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -C 1-6 alkyl, -O-C ⁇ alkyl, -S-d-6alkyl, -NR 37 R 38 ;
  • Ar 2 , Ar 3 , Ar 4 , Ar 5 , and Ar 6 are each independently a 5- or 6-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar Ar 2 , Ar 3 , Ar 4 , and Ar 5 being optionally and independently substituted with from 1 to 3 substituents selected from -NR 19 R 2 o, -C 1-6 alkyl, -0-Ci -6 alkyl, -S-Ci. 6 alkyl;
  • Het ! , Het 2 , Het 3 , Het 4 , Het 5 personally and Het 6 are each independently a 5-or 6-membered monocyclic heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each heterocycle is being optionally and independently substituted with from 1 to 3 substituents selected from -halo, — C 1-6 alkyl, -OC ⁇ alkyl, -SC ⁇ alkyl, -NR 21 R 22 ; each of said — Ct -6 alkyl being optionally substituted with from 1 to 3 -halo;
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N
  • the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, wherein
  • AT and A 2 are selected from C and N; wherein when A is C, then A 2 is N; and wherein when A 2
  • R 4 is selected from -halo, -OH, -Ci -6 alkyl, -O-C L ealkyl, -S-C 1-6 alkyl, -NR 17 R 18 , -Het 4 ;
  • R 5 and R 7 are each independently selected from -H, -halo, -Ci -6 alkyl, -OC ⁇ alkyl, -S-Ci. 6 alkyl, - Het 5 , -An, -C 3 .
  • R 3 6, R 3 7, R 38 , R 3 9 and R 40 are each independently selected from -H, -halo, -O, -OH, -O-C ⁇ alkyl, -C ⁇ alkyl, -C 3 . 6 cycloalkyl or -Het-i ; wherein each of said d- 6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-d.ealkyl, -S-d. 6 alkyl, -Het 6 , -Ar 5 ;
  • Ar-i , Ar 2 , Ar 3 , Ar 4 , Ar 5 , and Ar 6 are each independently a 5- or 6-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said An, Ar 2 , Ar 3 , Ar 4 , and Ar 5 being optionally and independently substituted with from 1 to 3 substituents selected from - NRi 9 R 20 , -d. 6 alkyl, -0-C 1-6 alkyl, -S-d-6alkyl;
  • Het ! , Het 2 , Het 3 , Het 4 , Het 5 , and Het 6 are each independently a 5-or 6-membered monocyclic heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each heterocycle is being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -d. 6 alkyl, -OC 1-6 alkyl, -Sd. 6 alkyl, -NR 2 i R 22 ; each of said— C 1-6 alkyl being optionally substituted with from 1 to 3 -halo;
  • Zi , Z 2 , Z 3 , Z 4 and Z 5 are each independently is selected from C and N
  • the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, wherein,
  • A- is N and A 2 is C;
  • R is selected from -H, -OH, -d-ealkyl, -C 3 . 6 cycloalkyl, -0-C 1-6 alkyl, -S-d. 6 alkyl, -NR 9 R 10 , -S0 2 - R 4 , -CN, -NR9-SO2-R4, -Het ! ; wherein each of said C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NRn R 12 , -O-C ⁇ alkyl, - S-d.
  • R 2 is selected from -H, -halo, -OH, -C 1-6 alkyl, -C 3 .
  • each of said C ⁇ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -O-C ⁇ alkyl, -S-C ⁇ alkyl, -Het 3 , -Ar 2 , -NR 13 Ri 4 ;
  • R 3 is selected from -H, -halo, -OH, -C 1-6 alkyl, -C 3 .
  • R 4 is selected from -halo, -OH, -C 1-6 alkyl, -0-Ci. 6 alkyl, -S-C 1-6 alkyl, -NR 17 R 18 , -Het 4 ;
  • R 5 and R 7 are each independently selected from -H, -halo, -C -6 alkyl, -OC ⁇ alkyl, -S-Ci -6 alkyl, - Hetg, -Ar,, -C 3 .
  • each of said C ⁇ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -OH, -OC 1-6 alkyl, -SC ⁇ alkyl, -Het 5 , -NR 25 R 26 ;
  • R231 R ⁇ 4> R251 R26.
  • R33, R3 , R35, R36, R37, R38, R39 and R 40 are each independently selected from -H, -halo, -O, -OH, -O-C ⁇ alkyl, -C 1-6 alkyl, -C 3 . 6 cycloalkyl or -Het-,; wherein each of said
  • 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -O-C ⁇ alkyl, -S-C 1-6 alkyl, -Het 6 , -Ar 5 ;
  • each of said C h alky! is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -C 1-6 alkyi, -0-C 1-6 alkyl, - S-C ⁇ alkyl, -NR 39 R 40 ;
  • Ar 2 , Ar 3 , Ar 4 , Ar 5 , and Ar 6 are each independently a 5- or 6-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar ⁇ Ar 2 , Ar 3 , Ar 4 , and Ar 5 being optionally and independently substituted with from 1 to 3 substituents selected from - NR 19 R 20 , -C 1-6 alkyl, -0-Ci.
  • Het 2 , Het 3 , Het 4 , Het 5 personally and Het 6 are each independently a 5-or 6-membered monocyclic heterocycle having from 1 to 3 heteroatoms selected from 0, N and S, wherein each heterocycle is being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -C ⁇ alkyl, -OC ⁇ alkyl, -SC ⁇ alkyl, -NR 2 R 22 ; each of said -C ⁇ alkyl being optionally substituted with from 1 to 3 -halo;
  • Z 2 , Z 3 , Z 4 and Z 5 are each C.
  • the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, wherein,
  • AT and A 2 are selected from C and N; wherein when A- is C, then A 2 is N; and wherein when A 2 is C, then is N;
  • R 2 is selected from -H and -C 1-6 alkyl; wherein each of said C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -OH, -0-Ci. 6 alkyl, -
  • R 3 is selected from -H and -C h alky!
  • R 4 is -NR 17 R 18 ;
  • R 5 and R 7 are each independently selected from -H, -C ⁇ alkyl; wherein each of said C ⁇ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, and -NR 23 R 24 ;
  • each of said C ⁇ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -OCi_ 6 alkyl, -Het 5 , -NR 25 R 26 ;
  • 4 , Ri7, Ri8. R23. R24, R25. R26. R31. R32, R34. and R 35 are each independently selected from
  • X 2 is selected from-O-Cvealkyl-, -S-C ⁇ ealkyl-, - R ⁇ C ⁇ ealkyl-;
  • Ar6 is a 5- or 6-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S;
  • Het 5 is a 5-or 6-membered monocyclic heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each heterocycle is being optionally and independently substituted with from 1 to 3 -C h alky!; each of said -C ⁇ alkyl being optionally substituted with from 1 to 3 -halo;
  • Z Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N
  • the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, wherein
  • RL R 2 , R 3 and R 5 are each -H;
  • R 25 and R 26 are each independently selected from -H, and -C -6 alkyl;
  • R 31 and R 32 are each-H
  • X ! is selected from-O-C ⁇ alkyl and -NRs-C ⁇ alkyl-;
  • X 2 is -NR 2 -Cv 6 alkyl-
  • Z Z 2 , Z 3 , Z and Z 5 are each C
  • the present invention provides a compound selected from the list comprising
  • the pyrazolopyrimidine moiety is linked to the aryl or heteroaryl moiety at position Z ⁇ or Z 2 , in accordance with the numbering as provided in Formula I, and/or R, is linked to the aryl or heteroaryl moiety at position Z 3 , Z 4 or Z 5 , in accordance with the numbering as provided in Formula I.
  • the present invention provides (pharmaceutical) compositions comprising a compound according to this invention.
  • the compounds and compositions according to this invention are suitable for use as a human or veterinary medicine.
  • the compounds and compositions according to this invention are suitable for inhibiting the activity of a kinase, in particular LRRK2 kinase, and may be used for the treatment and/or prevention of neurological disorders such as Alzheimer's disease or Parkinson's disease.
  • the present invention provides a method for the prevention and/or treatment of a neurological disorder, such as Alzheimer's disease or Parkinson's disease; said method comprising administering to a subject in need thereof a compound or a composition according to this invention.
  • the present invention provides compounds of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N- oxide form, or solvate thereof
  • A-i and A 2 are selected from C and N; wherein when A-i is C, then A 2 is N; and wherein when A 2 is C, then is N;
  • each of said C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, - NR R-12, -0-C 1-6 alkyl, -S-C 1-6 alkyl;
  • R 3 is selected from -H, -halo, -OH, -C 1-6 alkyl, -C 3 .
  • R 4 is selected from -halo, -OH, -C -6 alkyl, -0-Ci. 6 alkyl, -S-Ci -6 alkyl, -NR 17 R 18 , -Het 4 ;
  • R9i R2O1 R2I 1 R ⁇ 2i R ⁇ i R26. 27.
  • R33. 34 > R35, 36- R37, 38, R39 and R 40 are each independently selected from -H, -halo, -O, -OH, -0-Ci_ 6 alkyl, -C 1-6 alkyl, -C 3 . 6 cycloalkyl or -Het ⁇ wherein each of said Ci. 6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -O-d-ealkyl, -S-C,. 6 alkyl, -Het 6 , -Ar 5 ;
  • each of said C ⁇ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -C 1-6 alkyl, -O-C ⁇ alkyl, -S-C ⁇ alkyl, -NR 37 R 38 ;
  • Ar,, Ar 2 , Ar 3 , Ar 4 , Ar 5 , and Ar 6 are each independently a 5- or 6-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said ⁇ , Ar 2 , Ar 3 , Ar 4 , and Ar 5 being optionally and independently substituted with from 1 to 3 substituents selected from -NR 19 R 20 , -C ⁇ alkyl, -O-d-ealkyl, -S-C ⁇ alkyl;
  • Het-i , Het 2 , Het 3 , Het 4 , Het 5 personally and Het 6 are each independently a 5-or 6-membered monocyclic heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each heterocycle is being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -C 1-6 alkyl, -OCi_ 6 alkyl, -SCi. 6 alkyl, -NR 21 R 22 ; each of said— C -6 alkyl being optionally substituted with from 1 to 3 -halo;
  • Z ⁇ , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N
  • B is such as the right part of the possible values of B (i.e.
  • X-i is such as the right part of the possible values of X ! (i.e.
  • X 2 is such as the right part of the possible values of X 2 (i.e. in particular (d. 6 alkyl)- from -0-d. 6 alkyl, -S-Ci.
  • alkyl by itself or as part of another substituent refers to fully saturated hydrocarbon radicals.
  • alkyl groups of this invention comprise from 1 to 6 carbon atoms.
  • Alkyl groups may be linear or branched and may be substituted as indicated herein.
  • the subscript refers to the number of carbon atoms that the named group may contain.
  • C h alky! means an alkyl of one to six carbon atoms.
  • alkyl groups are methyl, ethyl, n-propyl, i-propyl, butyl, and its isomers (e.g.
  • C C 6 alkyl includes all linear, branched, or cyclic alkyl groups with between 1 and 6 carbon atoms, and thus includes methyl, ethyl, n-propyl, i-propyl, butyl and its isomers (e.g. n-butyl, i-butyl and t-butyl); pentyl and its isomers, hexyl and its isomers, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • optionally substituted alkyl refers to an alkyl group optionally substituted with one or more substituents (for example 1 to 3 substituents, for example 1 , 2 or 3 substituents or 1 to 2 substituents) at any available point of attachment.
  • substituents include -halo, -OH, primary and secondary amides, -O-C ⁇ alkyl, ⁇ -C ⁇ alky!, heteroaryl, aryl, and the like.
  • cycloalkyl by itself or as part of another substituent is a cyclic alkyl group, that is to say, a monovalent, saturated, or unsaturated hydrocarbyl group having a cyclic structure.
  • Cycloalkyl includes all saturated or partially saturated (containing 1 or 2 double bonds) hydrocarbon groups having a cyclic structure. Cycloalkyl groups may comprise 3 or more carbon atoms in the ring and generally, according to this invention comprise from 3 to 6 atoms. Examples of cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • alkyl groups as defined are divalent, i.e., with two single bonds for attachment to two other groups, they are termed "alkylene” groups.
  • alkylene groups includes methylene, ethylene, methylmethylene, trimethylene, propylene, tetramethylene, ethylethylene, 1 ,2-dimethylethylene, pentamethylene and hexamethylene.
  • alkylene groups of this invention preferably comprise the same number of carbon atoms as their alkyl counterparts. Where an alkylene or cycloalkylene biradical is present, connectivity to the molecular structure of which it forms part may be through a common carbon atom or different carbon atom. To illustrate this applying the asterisk nomenclature of this invention, a C 3 alkylene group may be for example * -CH 2 CH 2 CH 2 - * , * -CH(-CH 2 CH 3 )- * , or *- CH 2 CH(-CH 3 )- * .
  • heterocycle as used herein by itself or as part of another group refer to non- aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3 to 6 membered monocyclic ring systems) which have at least one heteroatom in at least one carbon atom- containing ring.
  • Each ring of the heterocyclic group containing a heteroatom may have 1 , 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms.
  • An optionally substituted heterocyclic refers to a heterocyclic having optionally one or more substituents (for example 1 to 4 substituents, or for example 1 , 2, 3 or 4), selected from those defined above for substituted alkyl.
  • heterocyclic groups include piperidinyl, azetidinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidyl, succinimidyl, 3H- indolyl, isoindolinyl, chromenyl, isochromanyl, xanthenyl, 2H-pyrrolyl, 1 -pyrrolinyl, 2-pyrrolinyl, 3- pyrrolinyl, pyrrolidinyl, 4H-quinolizinyl, 4aH-carbazolyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, pyranyl, dihydro-2H-pyranyl, 4H-pyranyl, 3,4- dihydro
  • aryl refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (i.e. phenyl).
  • Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated herein.
  • Non-limiting examples of aryl comprise phenyl, biphenylyl, biphenylenyl, 5- or 6-tetralinyl, 1 -, 2-, 3-, 4-, 5-, 6-, 7-, or 8-azulenyl, 1 - or 2-naphthyl, 1 -, 2-, or 3-indenyl, 1 -, 2-, or 9-anthryl, 1 - 2-, 3-, 4-, or 5-acenaphtylenyl, 3-, 4-, or 5- acenaphtenyl, 1 -, 2-, 3-, 4-, or 10-phenanthryl, 1 - or 2-pentalenyl, 1 , 2-, 3-, or 4-fluorenyl, 4- or 5-indanyl, 5-, 6-, 7-, or 8-tetrahydronaphthyl, 1 ,2,3,4-tetrahydronaphthyl, 1 ,4-dihydronaphthyl, dibenzo
  • the aryl ring can optionally be substituted by one or more substituents.
  • An "optionally substituted aryl” refers to an aryl having optionally one or more substituents (for example 1 to 5 substituents, for example 1 , 2, 3 or 4) at any available point of attachment, selected from those defined above for substituted alkyl.
  • heteroaryl ring where a carbon atom in an aryl group is replaced with a heteroatom, the resultant ring is referred to herein as a heteroaryl ring.
  • heteroaryl refers but is not limited to 5 to 6 carbon-atom aromatic rings in which one or more carbon atoms can be replaced by oxygen, nitrogen or sulfur atoms.
  • Non-limiting examples of such heteroaryl include: pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1 -b][1 ,3]thiazolyl, thieno[3,
  • an “optionally substituted heteroaryl” refers to a heteroaryl having optionally one or more substituents (for example 1 to 4 substituents, for example 1 , 2, 3 or 4), selected from those defined above for substituted alkyl.
  • halo or halogen as a group or part of a group is generic for fiuoro, chloro, bromo, or iodo, as well as any suitable isotope thereof.
  • substituted is meant to indicate that one or more hydrogens on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group, provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic and/or diagnostic agent.
  • groups may be optionally substituted, such groups may be substituted once or more, and preferably once, twice or thrice.
  • Substituents may be selected from, those defined above for substituted alkyl.
  • alkyl, aryl, or cycloalkyl each being optionally substituted with” or “alkyl, aryl, or cycloalkyl, optionally substituted with” refers to optionally substituted alkyl, optionally substituted aryl and optionally substituted cycloalkyl.
  • the compounds of the invention may exist in the form of different isomers and/or tautomers, including but not limited to geometrical isomers, conformational isomers, E/Z-isomers, stereochemical isomers (i.e. enantiomers and diastereoisomers) and isomers that correspond to the presence of the same substituents on different positions of the rings present in the compounds of the invention. All such possible isomers, tautomers and mixtures thereof are included within the scope of the invention.
  • the invention includes isotopically-labelled compounds and salts, which are identical to compounds of formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.
  • isotopes that can be incorporated into compounds of formula (I) are isotopes of hydrogen, carbon, nitrogen, fluorine, such as 3 H, 11 C, 13 N, 14 C, 15 0 and 18 F.
  • Such isotopically-labelled compounds of formula (I) are useful in drug and/or substrate tissue distribution assays.
  • 11 C and 18 F isotopes are particularly useful in PET (Positron Emission Tomography). PET is useful in brain imaging.
  • Isotopically labeled compounds of formula (I) can generally be prepared by carrying out the procedures disclosed below, by substituting a readily available non-isotopically labeled reagent with an isotopically labeled reagent.
  • the term "compounds of the invention” or a similar term is meant to include the compounds of general Formula I and any subgroup thereof. This term also refers to the compounds as depicted in Table 1 , their derivatives, W-oxides, salts, solvates, hydrates, stereoisomeric forms, racemic mixtures, tautomeric forms, optical isomers, analogues, pro-drugs, esters, and metabolites, as well as their quaternized nitrogen analogues.
  • the N- oxide forms of said compounds are meant to comprise compounds wherein one or several nitrogen atoms are oxidized to the so-called /V-oxide.
  • a compound means one compound or more than one compound.
  • a t and A 2 are selected from C and N; wherein when A ! is C, then A 2 is N; and wherein when A 2
  • a 2 is C.
  • a 2 is N and is C.
  • is selected from -H, -halo, -OH, -C h alky!, -C 3 . 6 cycloalkyl, -0-C 1-6 alkyl, -S-d- 6 alkyl, -NR 9 R 10 , -(C 0)-R 4 , -S0 2 -R 4 , -CN, -NR 9 -S0 2 -R 4 , -Het ⁇ wherein each of said C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR R 12 , -0-C 1-6 alkyl, -S-Ci -6 alkyl.
  • R 2 is selected from -H and -C 1-6 alkyl; wherein each of said C ⁇ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -OH, -O- C ⁇ alky!, -NR 13 R 14 .
  • R 2 is H.
  • R 3 is selected from -H and -C ⁇ alkyl
  • R 3 is H.
  • R 4 is selected from -halo, -OH, -C 1-6 alkyl, -0-C 1-6 alkyl, -S-Ci -6 alkyl, -NR 17 R 18 , -Het 4 . More preferably, R 4 is -NR 17 R 18 ;
  • R 5 and R 7 are each independently selected from -H, -halo, -C 1-6 alkyl, -OCi -6 alkyl, - S-C 1-6 alkyl, -Het 5 , -Ar -C 3 .
  • R 5 and R 7 are each independently selected from -H, -C 1-6 alkyl; wherein each of said d ⁇ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, and -NR 23 R 24 ;
  • R 5 and R 7 are each -H.
  • R 9 , R 0 , Rn, R12, Ri 3 , R14. is> R16. R17. R18. R19. R20. R21 ! R22. R23. R241 R27.
  • R 28 , R 29 , R 30 , R31 , R32, F1 ⁇ 2, R34, R35- R36, Re?, R38, R39 and R 40 are each independently selected from -H, -halo, -O, -OH, - ⁇ -d-ealkyl, -d-6alkyl, -C 3 .
  • each of said C ⁇ alkyl is optionally arid independently substituted with from 1 to 3 substituents selected from -halo, -OH, -O-Cvealkyl, -S-C 1-6 alkyl, -Het 6> -Ar 5 .
  • R32, R34- and R 35 are each independently selected from -H, -C 1-6 alkyl, and -C 3 . 6 cycloalkyl.
  • More preferably, is selected from -O-d-ealkyl-, -NR 3 -(C 0)-C 1-6 alkyl, -(C ⁇ - R ⁇ Cvealkyl-, -NR 3 -d- 6 alkyl-, -d- 6 alkyl-NR 3 -d- 6 alkyl-, -S0 2 -NR 3 -; wherein each of said C ⁇ alkyl is optionally and independently substituted with from 1 to 3 -C 1-6 alkyl.
  • X 2 is selected from -d- 6 alkyl-, -O-C ⁇ alkyl-, -0-Ci. 6 alkyl-0-Ci. 6 alkyl-, -S-C-
  • X 2 is selected from-O-C ! ⁇ alkyl-, -S-Ci. 6 alkyl-, -NR 2 -C 1 . 6 alkyl-.
  • X 2 is -NR 2 -C 1 . 6 alkyl-.
  • An , Ar 2 , Ar 3 , Ar 4 , Ar 5 , and Ar 6 are each independently a 5- or 6-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said An , Ar 2 , Ar 3 , Ar 4 , and Ar 5 being optionally and independently substituted with from 1 to 3 substituents selected from -NR 19 R 20 , -C -6 alkyl, -0-d. 6 alkyl, -S-d. 6 alkyl. More preferably, Ar 6 is a 5- or 6-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S.
  • Het-i, Het 2 , Het 3 , Het 4 , Het 5 personally and Het 6 are each independently a 5-or 6-membered monocyclic heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each heterocycle is being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -C 1-6 alkyl, -OC ⁇ alkyl, -SC 1-6 alkyl, -NR 21 R 22 ; each of said— C 1-6 alkyl being optionally substituted with from 1 to 3 -halo.
  • Het 5 is a 5-or 6-membered monocyclic heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each heterocycle is being optionally and independently substituted with from 1 to 3— C 1-6 a!kyl; each of said -C ⁇ alkyl being optionally substituted with from 1 to 3 -halo.
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N.
  • Z Z 2 , Z 3 , Z 4 and Z 5 are each C.
  • the present invention provides compounds of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof
  • AT and A 2 are selected from C and N; wherein when A- ! is C, then A 2 is N; and wherein when A 2 is C, then A ( is N;
  • each of said C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -O-C ⁇ alkyl, -S-C 1-6 alkyl, -Het 3l -Ar 2 , -NR 13 R 14 ;
  • R 3 is selected from -H, -halo, -OH, -C 1-6 alkyl, -C 3 . 6 cycloalkyl, -0-Ci.
  • each of said C -6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -OC ⁇ alkyl, -SC ⁇ alkyl, -NRi 5 R 16 , -Het 2 , -Ar 4 ;
  • R 4 is selected from -halo, -OH, -C ⁇ alkyl, -0-C,. 6 alkyl, -S-C 1-6 alkyl, -NR 17 R 18 , -Het 4 ;
  • Ci -6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -OC 1-6 alkyl, -SCi. 6 alkyl, -Het 5 , -NR 25 R 26 ;
  • Rl8 Rl9. 20> R21 > R22. R ⁇ 3 . 24. R25> R26. R27> R28» R ⁇ 9>
  • R 3 o, R31 , R32- R33, R34, R35, R36, R37, R3s > R39 and R 40 are each independently selected from -H, -halo, -O, -OH, -0-C -6 alkyr, -C 1-6 alkyl, -C 3 . 6 cycloalkyl or -Heti; wherein each of said d- 6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-C 1-6 alkyl, -S-C 1-6 alkyl, -Het 6 , -Ar 5 ;
  • Ar- ⁇ , Ar 2 , Ar 3 , Ar 4( Ar 5 , and Ar 6 are each independently a 5- or 6-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said ⁇ , Ar 2 , Ar 3 , Ar 4 , and Ar 5 being optionally and independently substituted with from 1 to 3 substituents selected from -NR 19 R 20 , -C 1-6 alkyl, -0-C 1-6 alkyl, -S-Ci. 6 alkyl;
  • Heti, Het 2 , Het 3 , Het 4 , Het 5 personally and Het 6 are each independently a 5-or 6-membered monocyclic heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each heterocycle is being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -C -6 alkyl, -OC 1-6 alkyl, -SCi. 6 alkyl, -NR 21 R 22 ; each of said— C 1-6 alkyl being optionally substituted with from 1 to 3 -halo;
  • Z Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N
  • the present invention provides compounds of Formula I wherein one or more of the following applies
  • a ⁇ and A 2 are selected from C and N; wherein when is C, then A 2 is N; and wherein when A 2 is C, then A, is N;
  • R 2 is selected from " -H and -C 1-6 alkyl; wherein each of said Chal y! is optionally and independently substituted with from 1 to 3 substituents selected from -OH, -O-C ⁇ alkyl, R 3 is selected from -H and -C 1-6 alkyl;
  • R 4 is -NR 17 R 18 ;
  • R 5 and R 7 are each independently selected from -H, -Ci -6 alkyl; wherein each of said C ⁇ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, and -NR 23 R 24 ;
  • each of said C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -OC 1-6 alkyl, -Het 5 , -NR 25 R 26 ;
  • R13, Ri 4 , Ri7, R18. R23, F>24 > Fi 25 , R 26 , R 3 i, R 32 , R 3 , and R 35 are each independently selected from -H, -C 1-6 alkyl, and -C 3 . 6 cycloalkyl;
  • X 2 is selected from-O-C ⁇ alkyl-, -S-C-
  • Ar 6 is a 5- or 6-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S;
  • Het 5 is a 5-or 6-membered monocyclic heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each heterocycle is being optionally and independently substituted with from 1 to 3 -Ci. 6 alkyl; . each of said -C h alky! being optionally substituted with from 1 to 3 -halo;
  • ZL Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N
  • the present invention provides compounds of Formula I wherein one or more of the following applies: A 1 is N and A 2 is C;
  • RL R 2 , R 3 and R 5 are each -H;
  • R 6 is selected from R 32 ,; wherein each of said C 1-6 alkyl is optionally and independently substituted with from 1 to 3 - R25R26;
  • R 25 and R 26 are each independently selected from -H, and -C -6 alkyl;
  • R 3 and R 32 are each-H
  • Xi is selected from-0-Ci. 6 alkyl and -NR 3 -d- 6 alkyl-;
  • X 2 is - R CLsalkyl-
  • Z Z 2 , Z 3 , Z and Z 5 are each C
  • Xi , and X 2 as used herein, represent biradicals, which taken together with the radicals to which they are attached form a macrocyclic pyrazolopyrimidine compound.
  • Said biradicals may be present in either of both directions in the macrocyclic pyrazolopyrimidine, but are preferably present in the direction as described below:
  • the present invention provides compounds of formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, wherein
  • a ⁇ and A 2 are selected from C and N; wherein when is C, then A 2 is N; and wherein when A 2
  • each of said C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -OC 1-6 alkyl, -SC ⁇ alkyl, -N 5 R 16 , -Het 2 , -Ar 4 ;
  • R 4 is selected from -halo, -OH, -C 1-6 alkyl, -0-C 1-6 alkyl, -S-C 1-6 alkyl, -NR 17 R 18 , -Het 4 ;
  • each of said Chalky! is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -OC ⁇ alkyl, -Sd-ealkyl, -Het 5 , -NR 25 R 26 ;
  • R9 R20. 2I . R22, R231 R24, 26. 271 R281 R ⁇ 9.
  • R37, R38- R39 and R 40 are each independently selected from -H, -halo, -O, -OH, -0-d. 6 alkyl, -C 1-6 alkyi, -C 3 . 6 cycloalkyl or -Het ⁇ wherein each of said d-
  • 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-d -6 alkyl, -S-d. 6 alkyl, -Het 6 , -Ar 5 ;
  • Ar Ar 2 , Ar 3 , Ar 4 , Ar 5 , and Ar 6 are each independently a 5- or 6-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar- ⁇ , Ar 2 ,
  • Ar 3 , Ar 4 , and Ar 5 being optionally and independently substituted with from 1 to 3 substituents selected from - NR 19 R 20 , -d. 6 alkyl, -0-C 1-6 alkyl, -S-C 1-6 alkyl;
  • Het! , Het 2 , Het 3 , Het 4 , Het 5 , and Het 6 are each independently a 5-or 6-membered monocyclic heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each heterocycle is being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -C 1-6 alkyl, -OC 1-6 alkyl, -SC ⁇ alkyl, -NR 21 R 22 ; each of said -C ⁇ alkyl being optionally substituted with from 1 to 3 -halo;
  • Z Z 2 , Z 3 , Z 4 and Z 5 are each independently is selected from C and N
  • the present invention provides compounds of formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, wherein
  • Ri is selected from -H, -OH, -C h alky!, -C 3 . 6 cycloalkyl, -O-C ⁇ alkyl, -S-C L ealk l, -NR 9 R 10 , -S0 2 - R 4 , -CN, -NR 9 -S0 2 -R , -Heti; wherein each of said C h alky! is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR R 12 , -O-C ⁇ alkyl, -S-C 1-6 alkyl;
  • R 4 is selected from -halo, -OH, -C 1-6 alkyl, -0-C 1-6 alkyl, -S-C 1-6 alkyl, -NR 17 R 18 , -Het 4 ;
  • each of said C-i. 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -OH, -OC 1-6 alkyl, -SCi. 6 alkyl, -Het 5 , -NR 25 R 26 ;
  • R 9 Rl0. l1. l2.
  • R30, R31 . R32. R33. R34> R35, R36, R37, R38, R39 and R 40 are each independently selected from -H, -halo, -O, -OH, -0-Ci- 6 alkyl, -C 1-6 alkyl, -C 3 . 6 cycloalkyl or ; wherein each of said 6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci.
  • each of said C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -C 1-6 alkyl, -0-C 1-6 alkyl, -S-Ci. 6 alkyl, -NR 37 R 3 8;
  • Ar ⁇ Ar 2 , Ar 3 , Ar 4 , Ar 5 , and Ar 6 are each independently a 5- or 6-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar-t, Ar 2 , Ar 3 , Ar 4 , and Ar 5 being optionally and independently substituted with from 1 to 3 substituents selected from - NR 19 R 20 , -C h alky!, -0-Ci -6 alkyl, -S-Ci. 6 alkyl;
  • Heti, Het 2 , Het 3 , Het 4 , Het 5 personally and Het 6 are each independently a 5-or 6-membered monocyclic heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each heterocycle is being optionally and independently substituted with from 1 to 3 substituents selected from -halo,— C 1-6 alkyl, -OC 1-6 alkyl, -SCi -6 alkyl, -NR 21 R 22 ; each of said -d_ 6 alkyl being optionally substituted with from 1 to 3 -halo;
  • the present invention provides compounds of formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, wherein
  • R- is selected from -H, -OH, -C 1-6 alkyl, -C 3 . 6 cycloalkyl, -O-C L ealkyl, -S-C 1-6 alkyl, -NR 9 R 10 , -S0 2 - R 4 , -CN, -NR 9 -S0 2 -R 4 , -He ⁇ ; wherein each of said C h lky! is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NRnR 12 , -O-C ⁇ alkyl, -S-d-ealkyl;
  • each of said C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-C 1-6 alkyl, -S-C ⁇ alkyl, -Het 3 , -Ar 2 , -NR 13 R 14 ;
  • each of said C ⁇ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -OC ⁇ alkyl, -SC 1-6 alkyl, -NR 15 R 16 , -Het 2 , -Ar 4 ;
  • R 4 is selected from -halo, -OH, -C h alky!, -0-d. 6 alkyl, -S-C 1-6 alkyl, -NR 17 R 18 , -Het 4 ;
  • R30, R31 . R32, Rs3> R34, R35> se, R37, R38, R39 and-R 40 are each independently selected from -H, -halo, -O, -OH, -O-C ⁇ alkyl, -C -6 alkyl, -C 3 . 6 cycloalkyl or -Het-i ; wherein each of said 6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-C 1-e alkyl, -S-C ⁇ alkyl, -Het 6 , -Ar 5 ;
  • each of said C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -C 1-6 alkyl, -0-C 1-6 alkyl, -S-C ⁇ alkyl, -NR 39 R 40 ;
  • Ar ⁇ Ar 2 , Ar 3 , Ar 4 , Ar 5 , and Ar 6 are each independently a 5- or 6-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar 1 ; Ar 2 , Ar 3 , Ar 4 , and Ar 5 being optionally and independently substituted with from 1 to 3 substituents selected from - NR 19 R 20 , -C 1-6 alkyl, -0-C 1 -6 alkyl, -S-C -6 alkyl;
  • Het ! , Het 2 , Het 3 , Het 4 , Het 5 ,, and Het 6 are each independently a 5-or 6-membered monocyclic heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each heterocycle is being optionally and independently substituted with from 1 to 3 substituents selected from -halo,— C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -NR 21 R 22 ; each of said -C ⁇ alkyl being optionally substituted with from 1 to 3 -halo;
  • Zi , Z 2 , Z 3 , Z 4 and Z 5 are each C.
  • the present invention provides compounds of formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, wherein AT and A 2 are selected from C and N; wherein when A-, is C, then A 2 is N; and wherein when A 2
  • R 2 is selected from -H and -C -6 alkyl; wherein each of said C h alky! is optionally and independently substituted with from 1 to 3 substituents selected from -OH, -0-C 1-6 alkyl, R 3 is selected from -H and -C-
  • R 4 is -NR 17 R 18 ;
  • R 5 and R 7 are each independently selected from -H, -C 1-6 alkyl; wherein each of said C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, and -NR 23 R 24 ;
  • each of said C ⁇ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -OCi. 6 alkyl, -Het 5 , -NR 25 R 26 ;
  • R23, 24, R25, R26- R31 , R32, R34. and R 35 are each independently selected from
  • X 2 is selected from-0-C 1-6 alkyl-, -S-C 1-6 alkyl-, -NR 2 -C 1 . 6 alkyl-;
  • Ar 6 is a 5- or 6-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S;
  • Het 5 is a 5-or 6-membered monocyclic heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each heterocycle is being optionally and independently substituted with from 1 to 3 -C 1-6 alkyl; each of said— C -6 alkyl being optionally substituted with from 1 to 3 -halo;
  • Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N
  • the present invention provides compounds of formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, wherein
  • RL R 2 , R 3 and R 5 are each -H;
  • R 25 and R 26 are each independently selected from -H, and -C h alky!; R 31 and R 32 are each-H
  • X-i is selected from-O-C ⁇ alkyl and -NRs-C ⁇ alkyl-;
  • X 2 is -NRg-d-ealkyl-
  • Z Z 2 , Z 3 , Z 4 and Z 5 are each C
  • the present invention provides a compound of formula II or stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, solvate thereof, wherein
  • R 5 and R 7 are each independently selected from -H, and -C h alky!,; wherein each of said d.
  • 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from
  • R25, 26, R31. and R 32 are each independently selected from -H, and -C 1-6 alkyl R35 is -C 3 . 6 cycloalkyl
  • Het 5 is a 5-or 6-membered monocyclic heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each heterocycle is being optionally and independently substituted with from 1 to 3— C 1-6 alkyl; each of said— C -6 alkyl being optionally substituted with from 1 to 3 -halo;
  • the present invention provides a compound of formula III or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, wherein
  • R 3 is selected from -H, and -C 1-6 alkyl
  • the present invention provides a compound of formula IV or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, wherein
  • R 3 is selected from -H, and -C ⁇ alkyl
  • R 6 is selected from wherein each of said C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -OC-
  • R 25 and R 26 are each -Ci -6 alkyl
  • the present invention provides a compound or stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, solvate thereof, selected from the list comprising:
  • the present invention provides a compound selected from the list comprising
  • the pyrazolopyrimidine moiety is linked to the aryl or heteroaryl moiety at position or Z 2 , in accordance with the numbering as provided in Formula I.
  • the of the compounds according to this invention is preferably linked to the aryl or heteroaryl moiety at position Z 3 , Z 4 or Z 5 , in accordance with the numbering as provided in Formula I.
  • the compounds of the present invention can be prepared according to the reaction schemes provided in the examples hereinafter, but those skilled in the art will appreciate that these are only illustrative for the invention and that the compounds of this invention can be prepared by any of several standard synthetic processes commonly used by those skilled in the art of organic chemistry.
  • the compounds of the present invention are useful in human or veterinary medicine, in particular for use as kinase inhibitors, more in particular for the inhibition of LRRK2 kinase.
  • the present invention further provides the use of a compound as defined hereinbefore or the use of a composition comprising said compound, as a human or veterinary medicine, in particular for the prevention and/or treatment of neurological disorders such as but not limited to Parkinson's disease and Alzheimer's disease.
  • the invention provides the use of a compound as defined hereinbefore or the use of a composition comprising said compound in the prevention and/or treatment of neurological disorders such as but not limited to Parkinson's disease and Alzheimer's disease.
  • the present invention further provides a compound as defined hereinbefore or a composition comprising said compound for use in the prevention and/or treatment of neurological disorders such as but not limited to Parkinson's disease and Alzheimer's disease.
  • a T and A 2 are selected from C and N; wherein when ⁇ ⁇ is C, then A 2 is N; and wherein when A 2 is C, then is N;
  • R 4 is selected from -halo, -OH, -C h alky!, -0-d. 6 alkyl, -S-d. 6 alkyl, -NR 17 R 18 , -Het 4 ;
  • Rl9i ⁇ 20 R21.
  • R38> R39 and R 40 are each independently selected from -H, -halo, -O, -OH, -0-Ci. 6 alkyl, -C 1-6 alkyl, -C 3 . 6 cycloalkyl or ; wherein each of said C-
  • each of said C -6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Chalky!, -0-Ci. 6 alkyl, -S-CLealkyl, -NR 39 R 4 o;
  • Ar-i , Ar 2 , Ar 3 , Ar 4 , Ar 5 , and Ar 6 are each independently a 5- or 6-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar ⁇ Ar 2 , Ar 3 , Ar 4 , and Ar 5 being optionally and independently substituted with from 1 to 3 substituents selected from -NR 19 R 20 , -C -6 alkyl, -0-C 1-6 alkyl, -S-C 1-6 alkyl;
  • Het-i , Het 2 , Het 3 , Het 4 , Het 5 personally and Het 6 are each independently a 5-or 6-membered monocyclic heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each heterocycle is being optionally and independently substituted with from 1 to 3 substituents selected from -halo, — C -6 alkyl, -OC ⁇ alkyl, -SC 1-6 alkyl, -NR 21 R 22 ; each of said -C ⁇ alkyl being optionally substituted with from 1 to 3 -halo;
  • ZL Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N
  • At and A 2 are selected from C and N; wherein when is C, then A 2 is N; and wherein when A 2
  • R 4 is selected from -halo, -OH, -d. 6 alkyl, -0-C 1-6 alkyl, -S-d-ealkyl, -NR 17 R, 8 , -Het 4 ;
  • R 5 and R 7 are each independently selected from -H, -halo, -C 1-6 alkyl, -OCi -6 alkyl, -S : Ci -6 alkyl,
  • Ci. 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -OC ⁇ .
  • each of said C 1 -6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -OC,.
  • R30, R31. Rs2, R33> R34, R 3 5, R36, R37, R38, R39 and R 40 are each independently selected from -H, -halo, -O, -OH, -0-d. 6 alkyl, -C -6 alkyl, -C 3 . 6 cycloalkyl or -Het-i ; wherein each of said 6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from
  • Z Z 2 , Z 3 , Z 4 and Z 5 are each independently is selected from C and N
  • A is N and A 2 is C;
  • each of said C 1-6 a(kyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NRnR 12 , -O-C ⁇ alkyl, -S-d-ealkyl;
  • R 2 is selected from -H, -halo, -OH, -C -6 alkyl, -C 3 .
  • R 3 is selected from -H, -halo, -OH, -d. 6 alkyl,
  • R 4 is selected from -halo, -OH, -C 1-6 alkyl, -O-C ⁇ alkyl, -S-d-ealkyl, -NR 17 R 18 , -Het 4 ;
  • R 5 and R 7 are each independently selected from -H, -halo, -d_ 6 alkyl, -OC 1-6 alkyl, -S-C ⁇ alkyl,
  • each of said C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -OH, -OC 1-6 alkyl, -SCi 6 alkyl, -Het 5 ,
  • R3i > R32.
  • R39 and R 40 are each independently selected from -H, -halo, -O, -OH, -0-d_ 6 alkyl, -d. 6 alkyl, -C 3 . 6 cycloalkyl or -Het ; wherein each of said d. 6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-d. 6 alkyl, -S-d. 6 alkyl, -Het 6 , -Ar 5 ; X!
  • each of said C ⁇ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -C 1-6 alkyl, -O-C ⁇ alkyl, -S-C ⁇ alkyl, -NR37R38;
  • each of said C ⁇ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -C 1-6 alkyl, -0-C 1-6 alkyl,
  • Ar Ar 2 , Ar 3 , Ar 4 , Ar 5 , and Ar 6 are each independently a 5- or 6-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said An , Ar 2 , Ar 3 , Ar 4 , and Ar 5 being optionally and independently substituted with from 1 to 3 substituents selected from - NR 19 R 20 , -C 1-6 alkyl, -S-C 6alkyl;
  • Heti, Het 2 , Het 3 , Het 4 , Het 5 personally and Het 6 are each independently a 5-or 6-membered monocyclic heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each heterocycle is being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -Chalky!, -OC 1-6 alkyl, -SC 1-6 alkyl, -NR 21 R 22 ; each of said -C ⁇ alkyl being optionally substituted with from 1 to 3 -halo;
  • Zi , Z 2 , Z 3 , Z 4 and Z 5 are each C.
  • Ai and A 2 are selected from C and N; wherein when A ⁇ is C, then A 2 is N; and wherein when A 2 is C, then A ⁇ is N;
  • R 2 is selected from -H, -C 1-6 alkyl; wherein each of said C 1-6 alkyl is optionally and independently substituted with from 1 to 3 -0-C 1-6 alkyl;
  • R 3 is selected from -H, -C ⁇ alkyl
  • R 4 is -NR 17 R 18 ;
  • R 5 and R 7 are each independently selected from -H, -C ⁇ alkyl; wherein each of said C ⁇ alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • R32, R34, R35, are each independently selected from -H, -Chalky!, -C 3 . 6 cycloalkyl;
  • X! is selected from
  • X 2 is selected from -NR 2 -Ci-6alkyl-;
  • Ar 6 is a 5- or 6-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S;
  • ZL Z 2 , Z 3 , Z 4 and Z 5 are each independently is selected from C and N.
  • AT and A 2 are selected from C and N; wherein when is C, than A 2 is N; and wherein when A 2 is C, than A, is N;
  • R 5 and R 7 are each independently selected from -H and -C -6 alkyl
  • Xi is -O-C ⁇ alkyl-; wherein when is -O-CH 3 -, then R 5 is not -H;
  • X 2 is - Rz-C ealkyl-
  • Z Z 2 , Z 3 , Z 4 and Z 5 are each C.
  • a pharmaceutical composition comprising a compound as defined in any one of statements 1 to 7, suitable for use as a human or veterinary medicine.
  • Compounds of formula (I) are inhibitors of LRRK2 kinase activity and are thus believed to be of potential use in the treatment of neurological disorders including Parkinson's disease, Alzheimer's disease, dementia (including Lewy body dementia and vascular dementia), age related memory dysfunction, mild cognitive impairment, argyrophilic grain disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, inherited frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), withdrawal symptoms/relapse associated with drug addiction, L-Dopa induced dyskinesia, and renal, breast, lung, prostate cancers as well as acute myelogenous leukemia (AML).
  • AML acute myelogenous leukemia
  • treatment of Parkinson's disease refers to the treatment of idiopathic Parkinson's disease and familial Parkinson's disease.
  • familial Parkinson's disease includes patients expressing LRRK2 kinase bearing the G2019S mutation or the R1441 G mutation.
  • Treatment of Parkinson's disease may be symptomatic or may be disease modifying.
  • treatment of Parkinson's disease refers to symptomatic treatment.
  • Compounds of the present invention may also be useful in treating patients identified as susceptible to progression to severe Parkinsonism by means of one of more subtle features associated with disease progression such as family history, olfaction deficits, constipation, cognitive defects, gait or biological indicators of disease progression gained from molecular, biochemical, immunological or Imaging technologies.
  • treatment may be symptomatic or disease modifying.
  • treatment of Alzheimer's disease refers to the treatment of idiopathic Alzheimer's disease and familial Alzheimer's disease.
  • Treatment of Alzheimer's disease may be symptomatic or may be disease modifying.
  • treatment of Alzheimer's disease refers to symptomatic treatment.
  • dementia including Lewy body dementia and vascular dementia
  • age related memory dysfunction mild cognitive impairment argyrophilic grain disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, inherited frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP- 7) and renal, breast, lung, prostate cancers as well as acute myelogenous leukemia (AML) may be symptomatic or disease modifying.
  • FTDP-7 chromosome 17
  • AML acute myelogenous leukemia
  • treatment of dementia including Lewy body dementia and vascular dementia
  • age related memory dysfunction mild cognitive impairment
  • argyrophilic grain disease Pick's disease
  • corticobasal degeneration progressive supranuclear palsy
  • progressive supranuclear palsy inherited frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP- 17)
  • FTDP- 17 inherited frontotemporal dementia and parkinsonism linked to chromosome 17
  • renal, breast, lung, prostate cancers as well as acute myelogenous leukemia (A L)
  • a L acute myelogenous leukemia
  • treatment of withdrawal symptoms/relapse associated with drug addiction and L-Dopa induced dyskinesia refers to symptomatic treatment.
  • the present invention further provides a method for the prevention and/or treatment of neurological disorders such as but not limited to Parkinson's disease and Alzheimer's disease, said method comprising administering to a subject in need thereof a therapeutic effective amount of a compound or a composition as defined herein.
  • the methods of the present invention can be utilized in a variety of settings, including, for example, in selecting the optimal treatment course for a patient, in predicting the likelihood of success when treating an individual patient with a particular treatment regimen, in assessing disease progression, in monitoring treatment efficacy, in determining prognosis for individual patients and in assessing predisposition of an individual to benefit from a particular therapy.
  • Said inhibition may be effected in vitro and/or in vivo, and when effected in vivo, is preferably effected in a selective manner, as defined above.
  • LRRK2 kinase-mediated condition or “disease”, as used herein, means any disease or other deleterious condition in which the LRKK2 kinase is known to play a role.
  • LRRK2 kinase-mediated condition or “disease” also means those diseases or conditions that are alleviated by treatment with a LRRK2 kinase inhibitor. Accordingly, another embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which the LRRK2 kinase is known to play a role.
  • the compounds of the invention may be used as a free acid or base, and/or in the form of a pharmaceutically acceptable acid-addition and/or base-addition salt (e.g. obtained with non-toxic organic or inorganic acid or base), in the form of a hydrate, solvate and/or complex, and/or in the form or a pro-drug or pre-drug, such as an ester.
  • a pharmaceutically acceptable acid-addition and/or base-addition salt e.g. obtained with non-toxic organic or inorganic acid or base
  • solvate includes any combination which may be formed by a compound of this invention with a suitable inorganic solvent (e.g. hydrates) or organic solvent, such as but not limited to alcohols, ketones, esters and the like.
  • suitable inorganic solvent e.g. hydrates
  • organic solvent such as but not limited to alcohols, ketones, esters and the like.
  • the pharmaceutically acceptable salts of the compounds according to the invention include the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases.
  • acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate,
  • Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth.
  • the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyi halides like benzyl and phenethyl-bromides and others.
  • Other pharmaceutically acceptable salts include the sulfate salt ethanolate and sulfate salts.
  • the compounds of the inventions may be formulated as a pharmaceutical preparation or pharmaceutical composition comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and optionally one or more further pharmaceutically active compounds.
  • such a formulation may be in a form suitable for oral administration, for parenteral administration (such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion), for administration by inhalation, by a skin patch, by an implant, by a suppository, etc..
  • Such suitable administration forms which may be solid, semi-solid or liquid, depending on the manner of administration - as well as methods and carriers, diluents and excipients for use in the preparation thereof, will be clear to the skilled person; reference is again made to for instance US-A-6, 372,778, US-A-6,369,086, US-A-6,369,087 and US-A-6,372,733, as well as to the standard handbooks, such as the latest edition of Remington's Pharmaceutical Sciences.
  • Such preparations include tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, creams, lotions, soft and hard gelatin capsules, suppositories, eye drops, sterile injectable solutions and sterile packaged powders (which are usually reconstituted prior to use) for administration as a bolus and/or for continuous administration, which may be formulated with carriers, excipients, and diluents that are suitable per se for such formulations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, (sterile) water, methylcellulose, methyl- and propy
  • the formulations can optionally contain other pharmaceutically active substances (which may or may not lead to a synergistic effect with the compounds of the invention) and other substances that are commonly used in pharmaceutical formulations, such as lubricating agents, wetting agents, emulsifying and suspending agents, dispersing agents, desintegrants, bulking agents, fillers, preserving agents, sweetening agents, flavoring agents, flow regulators, release agents, etc..
  • the compositions may also be formulated so as to provide rapid, sustained or delayed release of the active compound(s) contained therein, for example using liposomes or hydrophilic polymeric matrices based on natural gels or synthetic polymers.
  • the present invention encompasses a pharmaceutical composition comprising an effective amount of a compound according to the invention with a pharmaceutically acceptable cyclodextrin.
  • co-solvents such as alcohols may improve the solubility and/or the stability of the compounds.
  • addition of salts of the compounds of the invention can be more suitable due to their increased water solubility.
  • the compounds may advantageously be used in the form of a spray, ointment or transdermal patch or another suitable form for topical, transdermal and/or intradermal administration.
  • compositions may be formulated in a pharmaceutical formulation comprising a therapeutically effective amount of particles consisting of a solid dispersion of the compounds of the invention and one or more pharmaceutically acceptable water-soluble polymers.
  • a solid dispersion defines a system in a solid state (as opposed to a liquid or gaseous state) comprising at least two components, wherein one component is dispersed more or less evenly throughout the other component or components.
  • a solid solution When said dispersion of the components is such that the system is chemically and physically uniform or homogenous throughout or consists of one phase as defined in thermodynamics, such a solid dispersion is referred to as "a solid solution”.
  • Solid solutions are preferred physical systems because the components therein are usually readily bioavailable to the organisms to which they are administered.
  • Suitable surface modifiers can preferably be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants. Preferred surface modifiers include nonionic and anionic surfactants.
  • a pharmaceutical composition whereby the compounds are incorporated in hydrophilic polymers and applying this mixture as a coat film over many small beads, thus yielding a composition with good bio-availability which can conveniently be manufactured and which is suitable for preparing pharmaceutical dosage forms for oral administration.
  • Materials suitable for use as cores in the beads are manifold, provided that said materials are pharmaceutically acceptable and have appropriate dimensions and firmness. Examples of such materials are polymers, inorganic substances, organic substances, and saccharides and derivatives thereof.
  • the preparations may be prepared in a manner known per se, which usually involves mixing at least one compound according to the invention with the one or more pharmaceutically acceptable carriers, and, if desired, in combination with other pharmaceutical active compounds, when necessary under aseptic conditions.
  • a manner known per se which usually involves mixing at least one compound according to the invention with the one or more pharmaceutically acceptable carriers, and, if desired, in combination with other pharmaceutical active compounds, when necessary under aseptic conditions.
  • the pharmaceutical preparations of the invention are preferably in a unit dosage form, and may be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule or in any other suitable single-dose or multi-dose holder or container (which may be properly labeled); optionally with one or more leaflets containing product information and/or instructions for use.
  • unit dosages will contain between 1 and 1000 mg, and usually between 5 and 500 mg, of the at least one compound of the invention, e.g. about 10, 25, 50, 100, 200, 300 or 400 mg per unit dosage.
  • the compounds can be administered by a variety of routes including the oral, rectal, ocular, transdermal, subcutaneous, intravenous, intramuscular or intranasal routes, depending mainly on the specific preparation used and the condition to be treated or prevented, and with oral and intravenous administration usually being preferred.
  • the at least one compound of the invention will generally be administered in an "effective amount", by which is meant any amount of a compound of Formula or any subgroup thereof that, upon suitable administration, is sufficient to achieve the desired therapeutic or prophylactic effect in the individual to which it is administered.
  • such an effective amount will usually be between 0.01 to 1000 mg per kilogram body weight day of the patient per day, more often between 0.1 and 500 mg, such as between 1 and 250 mg, for example about 5, 10, 20, 50, 100, 150, 200 or 250 mg, per kilogram body weight day of the patient per day, which may be administered as a single daily dose, divided over one or more daily doses, or essentially continuously, e.g. using a drip infusion.
  • the amount(s) to be administered, the route of administration and the further treatment regimen may be determined by the treating clinician, depending on factors such as the age, gender and general condition of the patient and the nature and severity of the disease/symptoms to be treated.
  • said pharmaceutical composition can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms.
  • the present invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly.
  • compositions of the present invention can be mixed with suitable additives, such as excipients, stabilizers, or inert diluents, and brought by means of the customary methods into the suitable administration forms, such as tablets, coated tablets, hard capsules, aqueous, alcoholic, or oily solutions.
  • suitable inert carriers are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, or starch, in particular, corn starch.
  • the preparation can be carried out both as dry and as moist granules.
  • Suitable oily excipients or solvents are vegetable or animal oils, such as sunflower oil or cod liver oil.
  • Suitable solvents for aqueous or alcoholic solutions are water, ethanol, sugar solutions, or mixtures thereof.
  • Polyethylene glycols and polypropylene glycols are also useful as further auxiliaries for other administration forms.
  • these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art.
  • compositions When administered by nasal aerosol or inhalation, these compositions may be prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
  • Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the compounds of the invention or their physiologically tolerable salts in a pharmaceutically acceptable solvent, such as ethanol or water, or a mixture of such solvents.
  • the formulation can also additionally contain other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers as well as a propellant.
  • the compound according to the invention if desired with the substances customary therefore such as solubilizers, emulsifiers or further auxiliaries are brought into solution, suspension, or emulsion.
  • the compounds of the invention can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection or infusion preparations.
  • Suitable solvents are, for example, water, physiological saline solution or alcohols, e.g. ethanol, propanol, glycerol, in addition also sugar solutions such as glucose or mannitol solutions, or alternatively mixtures of the various solvents mentioned.
  • the injectable solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1 ,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
  • suitable non-toxic, parenterally-acceptable diluents or solvents such as mannitol, 1 ,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
  • these formulations When rectally administered in the form of suppositories, these formulations may be prepared by mixing the compounds according to the invention with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
  • a suitable non-irritating excipient such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
  • the compounds and compositions of the invention are used orally or parenterally.
  • the compounds of this invention can be prepared by any of several standard synthetic processes commonly used by those skilled in the art of organic chemistry.
  • the compounds are generally prepared from starting materials which are either commercially available or prepared by standard means obvious to those skilled in the art.
  • the compounds of formula (I) can be prepared as shown in scheme 1 below wherein a pyrazolo[1 ,5-a]pyrimidine or a imidazo[2,1 -f]pyridazine of formula (II) is converted by reaction with a compound of formula (III) into a compound of formula (IV), which is then reacted with a (hetero-) aryl of formula (V) to form a compound of formula (VI).
  • the compound of formula (VI) can then be optionally deprotected if desired before cyclisation to form a compound of formula (VII).
  • the compound of formula (VII) can be optionally converted into a compound of general formula (I).
  • LG-t and LG 2 each independently represent suitable leaving or functional groups
  • E represents a suitable functional group that can be used to form a direct bond between the (hetero-)aryl group and the scaffold.
  • D represents a functional group such as B or a protected functional group, which upon further reaction and/or deprotection produces a functional group such as B as defined in formula I;
  • the leaving groups LG, and LG 2 are advantageously a halo group such as a chlorine or a bromine group.
  • the reaction can be affected by a substitution for example by treating the compound of formula (II) with the compound of formula (III) in an organic solvent such as acetonitrile with an appropriate base such as for example diisopropylethylamine at an elevated temperature for example under reflux.
  • the protection reactions can be effected using for example isoindoline- 1 ,3-dione in a solvent such as toluene at an elevated temperature for example reflux or it can be effected by using for example tert-butoxycarbonyl anhydride in the presence of a base for example triethylamine in a solvent such as tetrahydrofuran at room temperature or it can be effected using for example tert-butyldimethylsilyl chloride and triethylamine in a solvent such as ⁇ , ⁇ -dimethylformamide at room temperature.
  • the deprotection reaction can be effected in a conventional manner using for example hydrazine in a solvent such as ethanol at an elevated temperature for example under reflux.
  • the compound of formula (IV) can optionally be protected with a suitable protecting group such as a tert-butyloxycarbonylamino group in a conventional manner for example by treatment with tert-butoxycarbonyl anhydride in basic conditions using for example triethylamine and 4-(dimethylamino)pyridine in a solvent such as tetrahydrofuran at an elevated temperature such as under reflux.
  • a suitable protecting group such as a tert-butyloxycarbonylamino group in a conventional manner for example by treatment with tert-butoxycarbonyl anhydride in basic conditions using for example triethylamine and 4-(dimethylamino)pyridine in a solvent such as tetrahydrofuran at an elevated temperature such as under reflux.
  • reaction of the resulting compound (IV) with a (hetero-)aryl compound of formula (V) is advantageously effected through the coupling of a boronic acid E or boronic ester E derivative of the (hetero-)aryl compound under Suzuki conditions using for example tetrakis(triphenylphosphine)palladium(0), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos) and potassium phosphate tribasic in a solvent mixture such as 1 ,4-dioxane/water at an elevated temperature for example 80°C.
  • a solvent mixture such as 1 ,4-dioxane/water at an elevated temperature for example 80°C.
  • the resulting compound of formula (VI) can optionally be treated to remove any desired protecting groups for example silyl ether groups such as tert-butyldimethylsilyl groups can be converted to the parent free hydroxy group.
  • any desired protecting groups for example silyl ether groups such as tert-butyldimethylsilyl groups can be converted to the parent free hydroxy group.
  • Such deprotection can be effected in a conventional manner for example using tetrabutylammonium fluoride in 1 ,4-dioxane at room temperature.
  • the cyclisation of the compound of formula (VI) can be effected for example under Mitsunobu conditions using for example diisopropyl azodicarboxylate and triphenylphosphine in a solvent mixture such as 2-methyl-1 ,4-dioxane and toluene at an elevated temperature such as 90°C.
  • the resulting compound of formula (VII) can optionally be treated to remove any desired protecting groups for example tert-butyloxycarbonylamino groups can be converted to the parent free amino group.
  • deprotection can be effected in a conventional manner for example by treatment under acidic conditions for example using a 4N hydrochloric acid solution in methanol at room temperature.
  • the deprotected compound can optionally be treated to form an amide compound of formula (I).
  • the reaction can advantageously be affected by treatment with an acylchloride and a base such as triethylamine in a solvent such as tetrahydrofuran at room temperature.
  • the reaction can also be affected using for example 0-(benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) and diisopropylethylamine in a solvent such as ⁇ , ⁇ -dimethylformamide at for example room temperature.
  • HBTU 0-(benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • the compounds of formula (I) can also be prepared as shown in general scheme 2 below wherein a pyrazolo[1 ,5-a]pyrimidine or a imidazo[2,1 -f]pyridazine of formula (II) is converted by reaction with a compound of formula (VIII) into a compound of formula (IX), which is then reacted with a (hetero-)aryl of formula (V) to form a compound of formula (X).
  • the compound of formula (X) can be reacted with a compound of formula (XI) to yield a compound of formula (XII).
  • the compound of formula (XII) can then be deprotected if desired before cyclisation to form a compound of formula (VII).
  • the compound of formula (VII) can be optionally converted into a compound of general formula (I).
  • LGi and LG 2 each independently represent suitable leaving or functional groups
  • E represents a suitable functional group that can be used to form a direct bond between the (hetero-)aryl group and the scaffold.
  • G and J represent functional groups or protected functional groups, which upon further reaction and/or deprotection produce a functional group such as D;
  • D represents a functional group such as B or a protected functional group, which upon further reaction and/or deprotection produces a functional group such as B as defined in formula I;
  • the leaving groups LG-i and LG 2 are advantageously a halo group such as a chlorine or a bromine group.
  • the reaction can be affected by a substitution for example by treating the compound of formula (II) with the compound of formula (VIII) in an organic solvent such as acetonitrile with an appropriate base such as for example diisopropylethylamine at an elevated temperature for example under reflux.
  • the resulting compound of formula (IX) can optionally be protected with a suitable protecting group such as a tert-butyloxycarbonylamino group in a conventional manner for example by treatment with tert-butoxycarbonyl anhydride in basic conditions using for example triethylamine and 4-(dimethylamino)pyridine in a solvent such as tetrahydrofuran at an elevated temperature such as under reflux.
  • a suitable protecting group such as a tert-butyloxycarbonylamino group in a conventional manner for example by treatment with tert-butoxycarbonyl anhydride in basic conditions using for example triethylamine and 4-(dimethylamino)pyridine in a solvent such as tetrahydrofuran at an elevated temperature such as under reflux.
  • reaction of the resulting compound (IX) with a (hetero-)aryl compound of formula (V) is advantageously effected through the coupling of a boronic acid E or boronic ester E derivative of the (hetero-)aryl compound under Suzuki conditions using for example tetrakis(tn ' phenylphosphine)palladium(0), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos) and potassium phosphate tribasic in a solvent mixture such as 1 ,4-dioxane/water at an elevated temperature for example 80°C.
  • a solvent mixture such as 1 ,4-dioxane/water at an elevated temperature for example 80°C.
  • reaction of the resulting compound of formula (X) with a compound of formula (XI) which can be advantageously effected under Williamson conditions using a base such as potassium carbonate in a solvent such as acetonitriie at an elevated temperature such as under reflux.
  • This reaction can also be effected under Mitsunobu conditions using for example diisopropyl azodicarboxylate and triphenylphosphine in a solvent such as tetrahydrofuran at an elevated temperature such as 90°C.
  • the resulting compound of formula (XII) can optionally be treated to remove any desired protecting groups for example tert-butyloxycarbonylamino groups can be converted to the parent free amino group and for example ester groups can be converted to the parent free carboxylic acid groups.
  • deprotection can be effected in a conventional manner for example by treatment under acidic conditions for example using an aqueous 6N hydrochloric acid solution in a solvent such as acetoniitrile at an elevated temperature for example 60°C or using an acid such as trifluoroacetic acid in a solvent such as dichloromethane at for example room temperature.
  • the cyclisation of the compound of formula (XII) can be effected for example by treatment with 0-(benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) and ⁇ , ⁇ -diisopropylethylamine in a solvent such as ⁇ , ⁇ -dimethylformamide at for example room temperature.
  • HBTU 0-(benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • the compounds of formula (I) can also be prepared as shown in general scheme 3 below wherein a pyrazolo[1 ,5-a]pyrimidine or a imidazo[2,1 -f]pyridazine of formula (II) is converted by reaction with a compound of formula (VIII) into a compound of formula (IX).
  • the compound of formula (IX) can be optionally be converted into a compound of formula (XIII) which is then reacted with a (hetero-)aryl of formula (XIV) to form a compound of formula (XV).
  • the compound of formula (XV) can then be optionally deprotected if desired before cyclisation to form a compound of formula (VII).
  • the compound of formula (VII) can be optionally converted into a compound of general formula (I).
  • LGi and LG 2 each independently represent suitable leaving or functional groups
  • E represents a suitable functional group that can be used to form a direct bond between the (hetero-)aryl group and the scaffold.
  • G represents a suitable functional group or protected functional group, which upon further reaction and/or deprotection produces a functional group such as K;
  • K and L represent functional groups or protected functional groups, which upon further reaction and/or deprotection produce a functional group such as D;
  • D represents a functional group such as B or a protected functional group, which upon further reaction and/or deprotection produces a functional group such as B as defined in formula I;
  • the leaving groups LG- ⁇ and LG 2 are advantageously a halo group such as a chlorine or a bromine group.
  • the reaction can be affected by a substitution for example by treating the compound of formula (II) with the compound of formula (VIII) in an organic solvent such as acetonitrile with an appropriate base such as for example diisopropylethylamine at an elevated temperature for example under reflux.
  • the compounds of formula (IX) can be deprotected using for example acidic conditions such as a 4N hydrochloric acid solution in methanol at room temperature.
  • the resulting deprotected compound can be reacted with for example 2-nitrobenzenesulfonyl chloride and triethylamine in a solvent such as dichloromethane at a temperature going from 0°C to room temperature.
  • the resulting compound can optionally be protected with a suitable protecting group such as a tert-butyloxycarbonylamino group in a conventional manner for example by treatment with tert-butoxycarbonyl anhydride in basic conditions using for example triethylamine and 4-(dimethylamino)pyridine in a solvent such as tetrahydrofuran at an elevated temperature such as under reflux.
  • a suitable protecting group such as a tert-butyloxycarbonylamino group in a conventional manner for example by treatment with tert-butoxycarbonyl anhydride in basic conditions using for example triethylamine and 4-(dimethylamino)pyridine in a solvent such as tetrahydrofuran at an elevated temperature such as under reflux.
  • the compound of formula (IX) can optionally be alkylated using for example iodomethane and cesium carbonate in a solvent such as ⁇ , ⁇ -dimethylformamide at a temperature such as room temperature.
  • the nitrobenzenesulfonyl can optionally be removed by treatment with for example thiophenol and cesium carbonate in a solvent such as ⁇ , ⁇ -dimethylformamide at for example room temperature.
  • the resulting compound can optionally be protected with a suitable protecting group such as a tert-butyloxycarbonylamino group in a conventional manner for example by treatment with tert- butoxycarbonyl anhydride in basic conditions using for example triethylamine and 4-(dimethylamino)pyridine in a solvent such as tetrahydrofuran at an elevated temperature such as under reflux.
  • a suitable protecting group such as a tert-butyloxycarbonylamino group in a conventional manner for example by treatment with tert- butoxycarbonyl anhydride in basic conditions using for example triethylamine and 4-(dimethylamino)pyridine in a solvent such as tetrahydrofuran at an elevated temperature such as under reflux.
  • the boronic ester of formula (XIV) can be obtained through for example Williamson reaction using for example potassium carbonate in a solvent such as acetonitrile at for example room temperature, followed by boronation through for example treatment with bis(pinacolato)diboron, [1 ,1 -bis(diphenylphosphino)ferrocene]dichloropalladium(ll) and potassium acetate in a solvent such as 1 ,4-dioxane at for example an elevated temperature such as 80°C.
  • Some intermediate steps can be required to obtain the desired boronic esters.
  • reaction of the compound with formula (XIII) with a (hetero-)aryl compound of formula (XIV) is advantageously effected under Suzuki conditions using for example tetrakis(triphenylphosphine)palladium(0), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos) and potassium phosphate tribasic in a solvent mixture such as 1 ,4-dioxane/water at an elevated temperature for example 80°C.
  • the resulting compound of formula (XV) can optionally be treated to remove any desired protecting groups for example tert-butyloxycarbonylamino groups can be converted to the parent free amino group and for example ester groups can be converted to the parent free carboxylic acid groups.
  • deprotection can be effected in a conventional manner for example by treatment under acidic conditions for example using an aqueous 6N hydrochloric acid solution in a solvent such as acetonitrile at an elevated temperature for example 60°C.
  • the cyclisation of the compound of formula (XV) can be effected for example by treatment with 0-(benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) and ⁇ , ⁇ -diisopropylethylamine in a solvent such as ⁇ , ⁇ -dimethylformamide at for example room temperature.
  • HBTU 0-(benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • the resulting compound of formula (VII) can optionally be treated to form a compound of formula (I).
  • the compounds of formula (I) can also be prepared as shown in general scheme 4 below wherein a pyrazolo[1 ,5-a]pyrimidine or a imidazo[2,1 -f]pyridazine of formula (II) is converted by reaction with a compound of formula (VIII) into a compound of formula (IX), which is then reacted with a (hetero-)aryl of formula (V) to form a compound of formula (X).
  • the compound of formula (X) can be reacted with a compound of formula (XI) to yield a compound of formula (XVI).
  • the compound of formula (XVI) can then be deprotected if desired before cyclisation to form a compound of formula (VII).
  • the compound of formula (VII) can be optionally converted into a compound of general formula (I).
  • LGT and LG 2 each independently represent suitable leaving or functional groups
  • E represents a suitable functional group that can be used to form a direct bond between the (hetero-)aryl group and the scaffold.
  • G and J represent functional groups or protected functional groups, which upon further reaction and/or deprotection produce a functional group such as D;
  • D represents a functional group such as B or a protected functional group, which upon further reaction and/or deprotection produces a functional group such as B as defined in formula I;
  • the leaving groups LG ⁇ and LG 2 are advantageously a halo group such as a chlorine or a bromine group.
  • the reaction can be affected by a substitution for example by treating the compound of formula (II) with the compound of formula (VIII) in an organic solvent such as acetonitrile with an appropriate base such as for example diisopropyl ethylamine at an elevated temperature for example under reflux.
  • the resulting compound of formula (IX) can optionally be protected with a suitable protecting group such as a tert-butyloxycarbonylamino group in a conventional manner for example by treatment with tert-butoxycarbonyl anhydride in basic conditions using for example triethylamine and 4-(dimethylamino)pyridine in a solvent such as tetrahydrofuran at an elevated temperature such as under reflux.
  • a suitable protecting group such as a tert-butyloxycarbonylamino group in a conventional manner for example by treatment with tert-butoxycarbonyl anhydride in basic conditions using for example triethylamine and 4-(dimethylamino)pyridine in a solvent such as tetrahydrofuran at an elevated temperature such as under reflux.
  • reaction of the resulting compound (IX) with a (hetero-)aryl compound of formula (V) is advantageously effected through the coupling of a boronic acid E or boronic ester E derivative of the (hetero-)aryl compound under Suzuki conditions using for example tetrakis(triphenylphosphine)palladium(0), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos) and potassium phosphate tribasic in a solvent mixture such as 1 ,4-dioxane/water at an elevated temperature for example 80°C.
  • a solvent mixture such as 1 ,4-dioxane/water at an elevated temperature for example 80°C.
  • the resulting compound of formula (X) can optionally be protected with a suitable protecting group such as a benzyl group in a conventional manner for example by treatment with benzylbromide in a solvent such as acetonitrile at an elevated temperature such as 80°C.
  • a suitable protecting group such as a benzyl group in a conventional manner for example by treatment with benzylbromide in a solvent such as acetonitrile at an elevated temperature such as 80°C.
  • the compounds of formula (IX) can be deprotected using for example acidic conditions such as a 4N hydrochloric acid solution in methanol at room temperature.
  • reaction of the resulting compound of formula (X) with a compound of formula (XI) which can be advantageously effected using a reagent such as 1 ,1 '-carbonyl diimdazole in a solvent such as tetrahydrofuran at a temperature such as room temperature.
  • reaction of the resulting compound of formula (X) with a compound of formula (XI) which can also be advantageously effected using a reagent such as sulfonylchloride and a base such as triethylamine in a solvent such as dichloromethane at a temperature such as room temperature.
  • a reagent such as sulfonylchloride and a base such as triethylamine in a solvent such as dichloromethane at a temperature such as room temperature.
  • the resulting compound of formula (XVI) can optionally be protected with a suitable protecting group such as a tert-butyloxycarbonylamino group in a conventional manner for example by treatment with tert-butoxycarbonyl anhydride in basic conditions using for example triethylamine and 4-(dimethylamino)pyridine in a solvent such as tetrahydrofuran at an elevated temperature such as under reflux.
  • a suitable protecting group such as a tert-butyloxycarbonylamino group in a conventional manner for example by treatment with tert-butoxycarbonyl anhydride in basic conditions using for example triethylamine and 4-(dimethylamino)pyridine in a solvent such as tetrahydrofuran at an elevated temperature such as under reflux.
  • the resulting compound of formula (XVI) can optionally be treated to remove any desired protecting groups such as benzyl groups which can be removed using a 1 N boron tribromide solution in a solvent such as dichloromethane at for example room temperature or by using palladium on activated charcoal under hydrogen atmosphere in a solvent mixture such as tetrahydrofuran/methanol at for example room temperature.
  • a solvent such as dichloromethane at for example room temperature
  • palladium on activated charcoal under hydrogen atmosphere in a solvent mixture such as tetrahydrofuran/methanol at for example room temperature.
  • the cyclisation of the compound of formula (VXl) can be effected for example by treatment with cesium carbonate, potassium iodide and tetrabutylammonium iodide at for example an elevated temperature such as 50°C or 90°C in a solvent such as ⁇ , ⁇ -dimethylacetamide or tetrahydrofuran.
  • the resulting compound of formula (VII) can optionally be treated to form a compound of formula (I).
  • reaction mixtures were magnetically stirred at room temperature. Where solutions were “dried”, they were generally dried over a drying agent such as sodium sulfate or magnesium sulfate. Where mixtures, solutions and extracts were “concentrated”, they were typically concentrated on a rotary evaporator under reduced pressure.
  • HPLC reversed phase high-performance liquid chromatography
  • the crude product was purified by reverse phase HPLC, using a Gilson semi-preparative HPLC system operated by Gilson UNIPOINT software.
  • the purification was carried out on a Phenomenex Luna column (100 mm long x 21 .2 mm i.d.; 5 ⁇ particles) at room temperature, with a constant flow rate of 20.0 mL/min.
  • a gradient elution was performed from 32% (25 mM NH4HC03 aqueous solution) / 68% (Acetonitrile-Methanol 1 :1 ) to 4% (25 mM NH4HC03 aqueous solution) / 96% (Acetonitrile-Methanol 1 :1 ) in 20 minutes.
  • the UV detector was set to 226nm, which corresponds to the wavelenght of maximum absorbance observed for the compound.
  • Example 1 is prepared following general scheme 1.
  • Example 2 is prepared following general scheme 2.
  • the reaction mixture was cooled, diluted with ethyl acetate and the organic layer was washed with brine. The organic layer was dried, filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using heptane and ethyl acetate as eluents. The product fractions were collected and the solvent was evaporated.
  • the reaction mixture was stirred at room temperature for 1 more hour after the addition was completed.
  • the mixture was quenched with 7N ammonia in methanol.
  • the solvent was removed under reduced pressure.
  • the residue was dissolved in dichloromethane and washed with a saturated sodium bicarbonate solution.
  • the aqueous layer was extracted with dichloromethane.
  • the combined organic layers were washed with brine, dried, filtered and the solvent was removed under reduced pressure.
  • the residue was purified by flash column chromatography over silica gel using dichloromethane and methanol as eluents. The product fractions were collected and the solvent was evaporated.
  • the residue was purified by flash column chromatography over silica gel using heptane and ethyl acetate as eluents (gradient elution from 0% to 50% ethyl acetate). The product fractions were collected and the solvent was evaporated.
  • the residue was purified by flash column chromatography over silica gel using heptane and ethyl acetate as eluents (gradient elution from 0% to 50% ethyl acetate). The product fractions were collected and the solvent was evaporated.
  • the reaction mixture was cooled, diluted with ethyl acetate and the organic layer was washed with brine. The organic layer was dried, filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using heptane and ethyl acetate as eluents. The product fractions were collected and the solvent was evaporated.
  • Diisopropyl azodicarboxylate (857 mg, 4.24 mmol) was added to a mixture of intermediate 12 (0.9 g, 2.0 mmol), tert-butyl N-(2-hydroxyethyl)carbamate (0.6 g, 3.8 mmol)) and triphenylphosphine (1.0 g, 3.8 mmol) in dry tetrahydrofuran (10 ml). The mixture was stirred at 90°C for 1 hour. The reaction mixture was cooled and the solvent was removed under reduced pressure.
  • the residue was purified by flash column chromatography over silica gel using hexane and ethyl acetate as eluents (gradient elution from 0% to 50% ethyl acetate). The product fractions were collected and the solvent was evaporated.
  • Example 4 is prepared following general scheme 1.
  • HBTU 0-(Benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • intermediate 6 was protected as a tert-butyldimethylsilyl chloride which was purified by HPLC.
  • a mixture of intermediate 16 (163 mg, 0.44 mmol), tert-butyldimethylsilyl chloride (100 mg, 0.66 mmol) and triethylamine (122 ⁇ , 0.88 mmol) in N,N-dimethylformamide (1.3 ml) was stirred at room temperature for 30 minutes.
  • the reaction mixture was diluted with ethyl acetate and washed with brine (3x).
  • the organic layer was dried, filtered and the solvent was removed under reduced pressure.
  • the residue was purified by reversed phase HPLC (HPLC method A). The product fractions were collected and the solvent was evaporated.
  • Example 5 is prepared following general scheme 3.
  • a mixture of 1 ,4-dioxane and water (3:1 , 7 ml) was degassed by bubbling nitrogen gas through the mixture.
  • Intermediate 22 (1.72 g, 3.66 mmol), intermediate 25 (1.2 g, 4.39 mmol), tetrakis(triphenylphosphine)palladium(0) (46 mg, 0.04 mmol), 2-dicyclohexylphosphino- 2',4',6'-triisopropylbiphenyl (Xphos) (72 mg, 0.15 mmol) and potassium phosphate tribasic (3.88 g, 5 eq.) were added and the mixture was stirred under nitrogen gas at 80°C for 2 hours.
  • the reaction mixture was cooled, diluted with ethyl acetate and the organic layer was washed with brine. The organic layer was dried, filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using heptane and ethyl acetate as eluents. The product fractions were collected and the solvent was evaporated.
  • the reaction mixture was stirred at room temperature for 1 more hour after the addition was completed.
  • the mixture was quenched with an aqueous solution of ammonia (25%).
  • the solvent was removed under reduced pressure and dichloromethane was added:
  • the organic layer was washed with a saturated sodium bicarbonate solution and the aqueous layer was extracted with dichloromethane.
  • the combined organic layers were washed with brine, dried, filtered and the solvent was removed under reduced pressure.
  • the residue was purified by flash column chromatography over silica gel using dichloromethane and methanol as eluents. The product fractions were collected and the solvent was evaporated.
  • the reaction mixture was cooled, diluted with ethyl acetate and the organic layer was washed with brine. The organic layer was dried, filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using heptane and ethyl acetate as eluents. The product fractions were collected and the solvent was evaporated.
  • the reaction mixture was stirred at room temperature for 1 more hour after the addition was completed.
  • the mixture was quenched with an aqueous solution of ammonia (25%).
  • the solvent was removed under reduced pressure and ethyl acetate was added.
  • the organic layer was washed with a saturated sodium bicarbonate solution and brine.
  • the organic layer was dried, filtered and the solvent was removed under reduced pressure.
  • the residue was purified by flash column chromatography over silica gel using dichloromethane and methanol as eluents. The product fractions were collected and the solvent was evaporated.
  • Example 8 is prepared following general scheme 4. Preparation of intermediate 39
  • Triethylamine (1.78 ml, 12.87 mmol) and 3-chloropropane-1 -surf onyl chloride (0.79 ml, 6.44 mmol) were added to a solution of intermediate 38 (1.7 g, 4.29 mmol) in dichloromethane (13 ml).
  • the reaction mixture was stirred at room temperature overnight.
  • More 3-chloropropane- 1 -sulfonyl chloride (0.26 ml, 2.14 mmol) was added and the reaction mixture was stirred at room temperature until completion.
  • the solvent was removed under reduced pressure and ethyl acetate was added.
  • the organic layer was washed with water, dried, filtered and the solvent was removed under reduced pressure.
  • the residue was purified by flash column chromatography over silica gel using hexane and ethylacetate as eluents. The product fractions were collected and the solvent was evaporated.
  • Example 9 is prepared following general scheme 1.
  • Example 10 is prepared following general scheme 1.
  • Example 1 is prepared following general scheme 1.
  • Ethyl carbonochloridate (100 ⁇ , 1.01 mmol) was added at 0°C to a solution of 7-oxa- 10,14,18,19,22- pentaazatetracyclo[13.5.2.1 ⁇ ⁇ 2,6 ⁇ .0 ⁇ ⁇ 18,21 ⁇ ]tricosa- 1 (21 ),2(23),3,5,15(22),16,19-heptaene hydrochloride (350 mg, 1.01 mmol) and triethylamine (349 ⁇ , 2.52 mmol) in dichloromethane (10 ml). The reaction mixture was stirred at room temperature for 1 hour. Water was added and the product was extracted with ethyl acetate.
  • Example 12 is prepared following general scheme 1 .
  • Example 13 is prepared following general scheme 1.
  • Methanesulfonyl chloride (45 ⁇ , 0.58 mmol) was added to a solution of 7-oxa-10, 3,17,18,21 - pentaazatetracyclo[12.5.2.1 ⁇ 2,6 ⁇ .0 A ⁇ 17,20 ⁇ ]docosa-1 (20),2,4,6(22),14(21 ),-15, 8-heptaene hydrochloride (175 mg, 0.527 mmol) and diisopropylethylamine (269 ⁇ , 1.58 mmol) in N,N- dimethylformamide (1.58 ml). The mixture was stirred at room temperature for 3 hours. Methanesulfonyl chloride (12 ⁇ , 0.16 mmol) was added and stirred at room temperature overnight. The solvent was removed under reduced pressure. Methanol was added. The precipitate was filtered and dried under reduced pressure.
  • Example 14 is prepared following general scheme 1.
  • Example 15 is prepared following general scheme 1.
  • HBTU 0-(Benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • Example 15 is prepared following general scheme 1.
  • Example 16 is prepared following general scheme 1 .
  • Example 17 is prepared following general scheme 1.
  • Example 18 is prepared following general scheme 1 .
  • HBTU O-(Benzotriazol-l -yl)- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethyluronium hexafluorophosphate
  • Example 19 is prepared following general scheme 1.
  • HBTU 0-(Benzotriazol-1 -yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate
  • Example 20 is prepared following general scheme 1.
  • HBTU 0-(Benzotriazol-1 -yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate
  • Example 21 is prepared following general scheme 1.
  • Cyclopropanesulfonyl chloride (81 mg, 0.58 mmol) was added to a solution of 7-oxa- 10,13,17,18,21 -pentaazatetracyclo[12.5.2.1 ⁇ 2,61.0 ⁇ 17,20 ⁇ ]docosa-1 (20),2,4,6(22),14(21 ),- 15,18-heptaene hydrochloride (175 mg, 0.527 mmol) and diisopropylethylamine (269 ⁇ , 1.58 mmol) in N,N-dimethylformamide (1.58 ml). The mixture was stirred at room temperature for 4 hours. Cyclopropanesulfonyl chloride (22 mg, 0.16 mmol) was added and stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. Methanol was added. The precipitate was filtered and dried under reduced pressure.
  • Example 22 is prepared following general scheme 1.
  • Example 23 is prepared following general scheme 1.
  • 2-morpholinoacetic acid hydrochloride (90 mg, 0.497 mmol) and N,N-diisopropylethylamine (384 ⁇ , 2.26 mmol) were dissolved in N,N-dimethylformamide (1.80 ml).
  • O-(Benzotriazol-l -yl)- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethyluronium hexafluorophosphate (HBTU) (205 mg, 0.54 mmol) was added and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and methanol was added. The precipitate was filtered and dried under reduced pressure.
  • Example 24 is prepared following general scheme 1. Preparation of intermediate 45
  • HBTU O-(Benzotriazol-l -yl)- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethyluronium hexafluorophosphate
  • Example 25 is prepared following general scheme 1.
  • Example 26 is prepared following general scheme 1 .
  • HBTU O-(Benzotriazol-l -yl)- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethyluronium hexafluorophosphate (HBTU) (205 mg, 0.54 mmol) was added and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and methanol was added. The mixture was stirred at room temperature for 1 hour. The precipitate was filtered and dried under reduced pressure. The product was taken up in dichloromethane/methanol (4:1 , 200 ml) and 4N HCI in 1 ,4-dioxane (84 ⁇ , 0.368 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the compound was triturated with diethyl ether, filtered and dried under reduced pressure.
  • HBTU O-(Benzotriazol-l -yl)- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethyluronium hex
  • Example 27 is prepared following general scheme 1 .
  • HBTU O-(Benzotriazol-l-yl)- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethyluronium hexafluorophosphate
  • Example 28 is prepared following general scheme 1.
  • Example 29 is prepared following general scheme 1. 7-oxa-10,13,17, 18,21 -pentaazatetracyclo[12.5.2.1 ⁇ 2,6 ⁇ . ⁇ 7,20 ⁇ ]docosa-

Abstract

La présente invention concerne de nouveaux composés macrocycliques et des compositions contenant lesdits composés agissant en tant qu'inhibiteurs de kinase, en particulier en tant qu'inhibiteurs de la LRRK2 (Leucine-Rich Repeat Kinase 2). En outre, la présente invention concerne des procédés de préparation des composés susmentionnés, ainsi que des méthodes d'utilisation desdits composés, par exemple en tant que médicament ou agent de diagnostic, en particulier pour le traitement et/ou le diagnostic de maladies caractérisées par une activité de la kinase LRRK2 telles que des troubles neurologiques y compris la maladie de Parkinson et la maladie d'Alzheimer.
PCT/IB2012/002318 2011-09-30 2012-09-28 Inhibiteurs macrocycliques de la kinase lrrk2 WO2013046029A1 (fr)

Priority Applications (15)

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EP12798824.4A EP2760453B1 (fr) 2011-09-30 2012-09-28 Inhibiteurs macrocycliques de la kinase lrrk2
AU2012314035A AU2012314035B2 (en) 2011-09-30 2012-09-28 Macrocyclic LRRK2 kinase inhibitors
CA2850350A CA2850350A1 (fr) 2011-09-30 2012-09-28 Inhibiteurs macrocycliques de la kinase lrrk2
UAA201404562A UA113186C2 (xx) 2011-09-30 2012-09-28 Макроциклічні інгібітори lrrk2 кінази
BR112014007654A BR112014007654A8 (pt) 2011-09-30 2012-09-28 Inibidores de lrrk2 quinase macrocíclicos.
MX2014003557A MX342177B (es) 2011-09-30 2012-09-28 Inhibidores de cinasa 2 de repeticion rica en leucina (lrrk2) macrociclica.
CN201280058430.8A CN104023728B (zh) 2011-09-30 2012-09-28 大环lrrk2激酶抑制剂
RU2014117515A RU2622104C2 (ru) 2011-09-30 2012-09-28 Макроциклические ингибиторы киназы lrrk2
KR1020147011284A KR20140095477A (ko) 2011-09-30 2012-09-28 마크로시클릭 lrrk2 키나제 억제제
JP2014532498A JP6082397B2 (ja) 2011-09-30 2012-09-28 マクロ環状ｌｒｒｋ２キナーゼ阻害剤
US14/348,138 US9096609B2 (en) 2011-09-30 2012-09-28 Macrocyclic LRRK2 kinase inhibitors
DK12798824.4T DK2760453T3 (en) 2011-09-30 2012-09-28 Macrocyclic LRRK2 kinase inhibitors
ES12798824.4T ES2583477T3 (es) 2011-09-30 2012-09-28 Inhibidores macrocíclicos de cinasa de LRRK2
HK15100389.2A HK1199838A1 (en) 2011-09-30 2015-01-14 Macrocyclic lrrk2 kinase inhibitors lrrk2
US14/747,882 US9370520B2 (en) 2011-09-30 2015-06-23 Macrocyclic LRRK2 kinase inhibitors

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WO2014140313A1 (fr) * 2013-03-15 2014-09-18 Oncodesign S.A. Inhibiteurs macrocycliques de la kinase inductible par un sel
WO2014140235A1 (fr) * 2013-03-15 2014-09-18 Ipsen Pharma S.A.S. Inhibiteurs macrocycliques de la kinase lrrk2
WO2015136073A1 (fr) * 2014-03-14 2015-09-17 Oncodesign Sa Inhibiteurs macrocycliques de la kinase tgf-br2
US9156845B2 (en) 2012-06-29 2015-10-13 Pfizer Inc. 4-(substituted amino)-7H-pyrrolo[2,3-d] pyrimidines as LRRK2 inhibitors
WO2016042089A1 (fr) * 2014-09-17 2016-03-24 Oncodesign S.A. Inhibiteurs macrocycliques de kinases lrrk2
JP2016517894A (ja) * 2013-05-06 2016-06-20 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ キナーゼ阻害剤としての大員環化合物
WO2016146651A1 (fr) 2015-03-16 2016-09-22 Oncodesign Sa Inhibiteurs macrocycliques de récepteur kinase de type activine
US9695171B2 (en) 2013-12-17 2017-07-04 Pfizer Inc. 3,4-disubstituted-1 H-pyrrolo[2,3-b]pyridines and 4,5-disubstituted-7H-pyrrolo[2,3-c]pyridazines as LRRK2 inhibitors
US10004751B2 (en) 2014-07-10 2018-06-26 The J. David Gladstone Institutes Compositions and methods for treating Dengue virus infection
US10039753B2 (en) 2015-09-14 2018-08-07 Pfizer Inc. Imidazo[4,5-c]quinoline and imidazo[4,5-c][1,5]naphthyridine derivatives as LRRK2 inhibitors
WO2018155947A1 (fr) 2017-02-24 2018-08-30 재단법인 대구경북첨단의료산업진흥재단 Composition pharmaceutique comprenant un composé apte à traverser la barrière hémato-encéphalique en tant que principe actif pour prévenir ou traiter le cancer du cerveau
WO2019012093A1 (fr) * 2017-07-14 2019-01-17 Glaxosmithkline Intellectual Property Development Limited Inhibiteurs de la kinase 2 à répétition riche en leucine
US10676486B2 (en) 2014-09-17 2020-06-09 Oncodesign S.A. Macrocyclic RIP2 kinase inhibitors
WO2022194976A1 (fr) * 2021-03-18 2022-09-22 Les Laboratoires Servier Inhibiteurs macrocycliques de la kinase lrrk2
WO2023076404A1 (fr) 2021-10-27 2023-05-04 Aria Pharmaceuticals, Inc. Méthodes de traitement de lupus érythémateux disséminé
WO2023073013A1 (fr) * 2021-10-27 2023-05-04 H. Lundbeck A/S Inhibiteurs de lrrk2
WO2023224894A1 (fr) * 2022-05-20 2023-11-23 Merck Sharp & Dohme Llc Macrocycles servant d'inhibiteurs de lrrk2, compositions pharmaceutiques et leurs utilisations
US11878987B2 (en) 2018-06-25 2024-01-23 Beijing Innocare Pharma Tech Co., Ltd. Heterocyclic compound as TRK inhibitor

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WO2013045653A1 (fr) * 2011-09-30 2013-04-04 Oncodesign S.A. Inhibiteurs de kinase flt3 macrocycliques
JP2019527230A (ja) * 2016-07-28 2019-09-26 ターニング・ポイント・セラピューティクス・インコーポレイテッドＴｕｒｎｉｎｇ Ｐｏｉｎｔ Ｔｈｅｒａｐｅｕｔｉｃｓ，Ｉｎｃ． 大環状キナーゼ阻害剤
JP2022505987A (ja) 2018-10-22 2022-01-14 エスカー セラピューティクス，インコーポレイテッド Ｔｙｋ２阻害剤およびその使用
CR20220561A (es) * 2020-05-06 2023-02-17 Servier Lab Nuevos inhibidores macrocíclicos de la quinasa de lrrk2
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US9156845B2 (en) 2012-06-29 2015-10-13 Pfizer Inc. 4-(substituted amino)-7H-pyrrolo[2,3-d] pyrimidines as LRRK2 inhibitors
US9642855B2 (en) 2012-06-29 2017-05-09 Pfizer Inc. Substituted pyrrolo[2,3-d]pyrimidines as LRRK2 inhibitors
US9586975B2 (en) 2013-03-15 2017-03-07 Oncodesign S.A. Macrocyclic salt-inducible kinase inhibitors
WO2014140313A1 (fr) * 2013-03-15 2014-09-18 Oncodesign S.A. Inhibiteurs macrocycliques de la kinase inductible par un sel
WO2014140235A1 (fr) * 2013-03-15 2014-09-18 Ipsen Pharma S.A.S. Inhibiteurs macrocycliques de la kinase lrrk2
WO2014140299A1 (fr) * 2013-03-15 2014-09-18 Oncodesign S.A Inhibiteurs macrocycliques de la kinase rip2
CN105143232A (zh) * 2013-03-15 2015-12-09 益普生制药股份有限公司 大环的lrrk2激酶抑制剂
US20160031905A1 (en) * 2013-03-15 2016-02-04 Ipsen Pharma S.A.S. Macrocyclic LRRK2 Kinase Inhibitors
JP2016517894A (ja) * 2013-05-06 2016-06-20 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ キナーゼ阻害剤としての大員環化合物
US9695171B2 (en) 2013-12-17 2017-07-04 Pfizer Inc. 3,4-disubstituted-1 H-pyrrolo[2,3-b]pyridines and 4,5-disubstituted-7H-pyrrolo[2,3-c]pyridazines as LRRK2 inhibitors
WO2015136073A1 (fr) * 2014-03-14 2015-09-17 Oncodesign Sa Inhibiteurs macrocycliques de la kinase tgf-br2
US10004751B2 (en) 2014-07-10 2018-06-26 The J. David Gladstone Institutes Compositions and methods for treating Dengue virus infection
EA032838B1 (ru) * 2014-09-17 2019-07-31 Онкодизайн С.А. Макроциклические ингибиторы lrrk2-киназы
WO2016042089A1 (fr) * 2014-09-17 2016-03-24 Oncodesign S.A. Inhibiteurs macrocycliques de kinases lrrk2
US10676486B2 (en) 2014-09-17 2020-06-09 Oncodesign S.A. Macrocyclic RIP2 kinase inhibitors
US10377772B2 (en) 2014-09-17 2019-08-13 Oncodesign S.A. Macrocyclic LRRK2 kinase inhibitors
AU2015316801B2 (en) * 2014-09-17 2019-03-07 Oncodesign S.A. Macrocyclic LRRK2 kinase inhibitors
WO2016146651A1 (fr) 2015-03-16 2016-09-22 Oncodesign Sa Inhibiteurs macrocycliques de récepteur kinase de type activine
US10039753B2 (en) 2015-09-14 2018-08-07 Pfizer Inc. Imidazo[4,5-c]quinoline and imidazo[4,5-c][1,5]naphthyridine derivatives as LRRK2 inhibitors
WO2018155947A1 (fr) 2017-02-24 2018-08-30 재단법인 대구경북첨단의료산업진흥재단 Composition pharmaceutique comprenant un composé apte à traverser la barrière hémato-encéphalique en tant que principe actif pour prévenir ou traiter le cancer du cerveau
WO2019012093A1 (fr) * 2017-07-14 2019-01-17 Glaxosmithkline Intellectual Property Development Limited Inhibiteurs de la kinase 2 à répétition riche en leucine
US11878987B2 (en) 2018-06-25 2024-01-23 Beijing Innocare Pharma Tech Co., Ltd. Heterocyclic compound as TRK inhibitor
WO2022194976A1 (fr) * 2021-03-18 2022-09-22 Les Laboratoires Servier Inhibiteurs macrocycliques de la kinase lrrk2
WO2023076404A1 (fr) 2021-10-27 2023-05-04 Aria Pharmaceuticals, Inc. Méthodes de traitement de lupus érythémateux disséminé
WO2023073013A1 (fr) * 2021-10-27 2023-05-04 H. Lundbeck A/S Inhibiteurs de lrrk2
US11780851B2 (en) 2021-10-27 2023-10-10 H. Lundbeck A/S LRRK2 inhibitors
WO2023224894A1 (fr) * 2022-05-20 2023-11-23 Merck Sharp & Dohme Llc Macrocycles servant d'inhibiteurs de lrrk2, compositions pharmaceutiques et leurs utilisations

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RU2014117515A (ru) 2015-11-10
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CN104023728B (zh) 2016-11-02
US9370520B2 (en) 2016-06-21
JP6082397B2 (ja) 2017-02-15
BR112014007654A2 (pt) 2018-04-17
AU2012314035B2 (en) 2016-12-15
US20150290198A1 (en) 2015-10-15
BR112014007654A8 (pt) 2018-06-12
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MX342177B (es) 2016-09-20
HK1199838A1 (en) 2015-07-24
US20140206683A1 (en) 2014-07-24
CN104023728A (zh) 2014-09-03
RU2622104C2 (ru) 2017-06-13
AU2012314035A1 (en) 2014-05-15
EP2760453B1 (fr) 2016-05-25
DK2760453T3 (en) 2016-08-15
US9096609B2 (en) 2015-08-04
CA2850350A1 (fr) 2013-04-04
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